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THE HARVEY SOCIETY

THE
HARVEY LECTURES
Delivered under the auspices of
THE HARVEY SOCIETY
OF NEW YORK

Previously Published

FIRST SERIES. 1905-1906
SECOND SERIES. 1906-19007
THIRD SERIES. 1907-1908
FOURTH SERIES. 1908-1909
FIFTH SERIES . 10909-1910
SIXTH SERIES . 1910-1911

«s The Harvey Society deserves
the thanks of the profession at large
for having organized such a series
and for having made it possible for
all medical readers to share the
profits of the undertaking.’’

—Medical Record, New York.
Crown 8vo. Cloth, $2.00 net, per volume.

J. B. LIPPINCOTT COMPANY
Publishers Philadelphia

THE HARVEY LECTURES

DELIVERED UNDER THE AUSPICES OF

THE HARVEY SOGCIEZY
OF NEW YORK

IQII-19Q12

BY
Dr. SIMON FLEXNER Pror. WALTER B. CANNON
Pror. ALBRECHT KOSSEL Pror. HENRY FAIRFIELD OSBORN
Pror. MAX VERWORN Pror. THEODORE WILLIAM RICHARDS
Pror. JAMES J. PUTNAM Pror. RUSSELL H. CHITTENDEN

Pror. WILLIAM T. SEDGWICK Pror. H. S. JENNINGS
Pror. WILLIAM SYDNEY THAYER

PHILADELPHIA AND LONDON

J. B. LIPPINCOTT COMPANY

“ ‘ty ”

Copyricut, 1912 en
By J. B. Lipprvcotr Company

tees
Sey.

OFFICERS AND MEMBERS OF THE SOCIETY

OFFICERS

Freperic 8. Lee, President

Wm. H. Parx, Vice-President
Epwarp K. DunHam, Treasurer

Haven Emerson, Secretary

COUNCIL

GRAHAM LUSK

S. J. MeurzEer

W. G. MacCatium
The Officers Ex Officio

ACTIVE MEMBERS

Dr. JoHn S. ADRIANCE

Dr. HucH AUCHINCLOSS
Dr. JOHN AUER

Dr. FREDERICK W. BANCROFT
Dr. SiuAs P. BEEBE

Dr. StTanteY R. BENEDICT
Dr. Hermann M. Bices
Dr. Harrow Brooks

Dr. Leo BUERGER

Dr. Russe~xL Burton-Opitz
Dr. E. E. Burrerrietp
Dr. ALEXIS CARREL

Dr. P. F. Cuark

Dr. A. F. Coca

Dr. ALFRED E. COHN

Dr. Rurus CoLe

Dr. H. D. DaxIn

Dr. CHARLES B. DAVENPORT
Dr. A. R. Docuez

Dr. GEORGE DRAPER

Dr. EvGenst F. Du Bors
Dr. Epwarp K. DunHAM
Dr. WituiAM J. ELSEer

Dr. Haven Emerson

Dr. James Ewina

Dr. Cyrus W. Frevp

Dr. Stmon FLEXNER

Dr. AustTIN FLINT

. Newuis B. Foster

. J. S. FURGUSON

. Witiiam J. GIEs

. T. S. GrrHEeNns

. FrepEeRIC M. HANES

. THomAas W. HASTINGS
. Ropert A. HATCHER

. Puttip Hanson Hiss, JR.
. JOHN HOWLAND

. G. S. Huntineron

. Hotmes C. JACKSON
. WALTER A. JACOBS

. THEODORE C. JANEWAY
» JAMES W. JOBLING

. Don R. JOSEPH

. Davip M. KAPLAN

. L. S. Kuerner

. RicHarpD V. LAMAR

. Ropert A. LAMBERT

. Freperic S. Les

. E. S. LESPERANCE

. PHasus A. LEVENE

. Isaac LEVIN

. KE. Lipman

. CHARLES C. LIEB

. W. T. Lonecorre

. GraHam Lusk

. J. F. McCLenDoN

Dr
Dr

. W. G. MacCattum
. ArTHUR R. MANDEL
. JOHN A. MANDEL

. F. S. MaAnpEeLBaum
. W. H. Manwarine

. S. J. MEurTzEer

. ADOLF MEYER

. GUSTAVE M. MEYER

. L. S. MILNE

. Herman O. MOSENTHAL
. J. R. Muruin

. Hipryo NoGucHti

. CHARLES NorRIS

. Horst OERTEL

. EUGENE L. Opie

. B. S. OPPENHEIMER
. WiuuiaAM H. ParK
. KF. W. PEApopy

ACTIVE MEMBERS—Continued.

W. J. McNEAL

. M. PEARCE
. MircHEeLL PRUDDEN

4h
. A. N. RicHarps
Cc

. G. Ropinson

. Peyton Rous

. Orro H. SCHULTZE

. H. D. SENIOR

2. HugH A. STEWART

. CHARLES R. STOCKARD
. ISRAEL STRAUSS

. Homer F. Swirt
BAT: Reeey

. J.C; Torrey

. DonatD D. VAN SLYKE
. Kart M. VOGEL

. AuGuSTUS WADSWORTH
. A. J. WAKEMAN

. GrorGE B. WALLACE

. RicHarp WEIL

. WinLIAM H. WELKER

. CARL J. WIGGERS

. ANNA W. WILLIAMS

. Ropert J. WILSON

. RupotpH A. WITTHAUS
. MartHa WOLLSTEIN

. FRANCIS
. JONATHAN WRIGHT

CARTER Woop

ASSOCIATE MEMBERS

. Ropert ABBE

. CHARLES Francis ADAMS
. IsAAc ADLER

. Frep H. ALBEE

. WILLIAM B. ANDERTON

. S. T. ARMSTRONG

. W. M. ARMSTRONG

. GorHAM BAcon

Dr.
Dr.
Dr.
Dr.

Prarce BAILEY
L. Bouton Banas

THEODORE B. BARRINGER, JR.

Simon BarucHe
A. W. BAstTEpo
Cart Beck

Dr.
Dr.
. ARTHUR BOOKMAN

. Davin Bovatrp, JR.

. JOHN W. BRANNAN

. JOSEPH BRETTAUER

. Georce E. BREWER

. SAMUEL M. BRICKNER
. NatHan E. Briuu

. Wu. B. BrINSMADE

. Epwarp B. BRONSON

. SAMUEL A. BROWN

. JOSEPH D. BRYANT

. JESSE G. M. BULLOWA

JosEPH A. BLAKE
Geo. BLUMER

Dr.
Dr.

ASSOCIATE MEMBERS—Continued.

GLENWoRTH R. BUTLER
C. N. B. Camac

. Wm. F. CAMPBELL

. Ropert J, CARLISLE

. Hersert S. CARTER

. ARTHUR F.. CHASE

. T. M. CHEESEMAN

. CORNELIUS G. COAKLEY
. Henry C. Cor

. WARREN COLEMAN

. WILLIAM B. CoLEYy

. CHARLES F. CoLuIns
. Lewis A. CoNNER

. Epwin B. CRAGIN

. Fuoyp M. CRANDALL
. GEORGE W. CRARY

. Conman W. CUTLER
. CHarLES L. Dana

. THoMAS DARLINGTON
. D. Bryson DELAVAN
. Epwarp B. DENCH
. W. K. DRAPER

. ALEXANDER DUANE

. THEODORE DUNHAM

. Max EINHORN

. CHARLES A. ELSBERG
. ALBERT A. EPSTEIN
. Evan M. Evans

. SAMUEL M. Evans

. Epwarp D. FISHER

. Roure FLoyp

. JOHN A. ForDYCE

. JOSEPH FRAENKEL

. Ropert T. FRANK

. RowLanp G. FREEMAN
. WoLFF FREUDENTHAL
. Lewis F. FRIsseLL

. ARPAD G. GERSTER
. Virgin P. GIBNEY

. Coartes L. Gipson

. J. RmpLE GOFFE
. SIGISMUND S. GOLDWATER
. MALCOLM GOODRIDGE

. NATHAN W. GREEN

. JAMES C. GREENWAY

. Emin GRUENING

. F. K. Hantock

. GrAEME M. Hammonp
. T. Stuart Harr

. FRANK HARTLEY

. JoHN A. HARTWELL

. JAMES R. HAYDEN

. Henry HEIMAN

. ALFRED FI’. HESS

. Augustus Hoc#

. AustTIN W. Ho.uis

. H. Srymour HouGHtTon
. FRANCIS HUBER

. JOHN H. HvuppLEston

. Epwarp L. Hunt

. Woops HutTcHINSON

. LEOPOLD JACHES

. ABRAM JACOBI

. GeorGeE W. JACOBY

. J. RALPH JACOBY

. WALTER B. JAMES

. SmirH Ey JELLIFFE

. FREDERIC KAMMERER

. Lupwia Kast

. JACOB KAUFMANN

. CHARLES GILMORE KERLEY
. Puiuip D. KERRISON

. Epwarp L. KrysEs

. Epwarp L. Keyes, JR.

. EveANOR B. KILHAM

. Orro KILIANt

. Francis P. KiInnicurr
. ARNOLD KNAPP

. Linnagus E. LA FEtra
. ALEXANDER LAMBERT

ASSOCIATE MEMBERS—Continued.

. SAMUEL W. LAMBERT
. Gustav LANGMANN

. BoLEsLAwW LAPOWSKI
. Burton J. Ler

. EcBert Le FrEvre

. CHarLes H. Lewis

. Rosert Lewis, JR.

. Ett Lone

. Winuiam C. Lusk

. HAM vie

. D. Hunter McApin
. CHARLES McBuRNEY
. JAMES F. McKernon
. GrorcE McNauGuTon
. Morris MANGES

. GrorGE MANNHEIMER
. WILBUR B. MARPLE

. Frank S. Meara

. ViIcTOR MELTZER

. WALTER MENDELSON
. ALFRED MEYER

. Witty Mryer

. MicHAarL MICHAILOVSKY
. GEORGE N. MILLER

. JAMES A. MILLER

. Ropert T. Morris

. ALEXIS V. MoscHow1tz
. JOHN P. MunNN

. ARCHIBALD MurRAY

. Van Horne Norrie

. Witi1Am P, Nortrurupe
,. NATHANIEL R. Norton
. AuFreD T. Oscoop

. Henry McM. PAIntTER
. ELEANOR PARRY

. Henry S. Partrerson
. Stewart Patron

. Georce L. PErasopy

. CHARLES H. Peck

. FREDERICK PETERSON
. Goprrey R. PiseK

. Witu1AM M. PoLK

. SIGISMUND POLLITZER

. NATHANIEL B. POTTER
. WILLIAM B. PRITCHARD
. WILLIAM J. PULLEY

. FRANCIS J. QUINLAN

. EDWARD QUINTARD

. A. F. Riaes

. ANDREW R. ROBINSON

. JOHN Rocers, JR.

. JOSEPH C. ROPER

. JULIUS RUDISCH

. BERNARD SACHS

. Tuomas E. SATreRTHWAITE
. ReGgiInaLD H. SAYRE

. Max G. ScHLApP

. Fritz ScHWyYZER

. E. W. ScRIPTURE

. Newton M. SHAFFER

. Montcomery H. Sicarp
. Henry MANN SILVER
. WiuuiAmM K. Simpson
. A, ALEXANDER SMITH

. FRED P. SOLLEY

. FREDERIC E. SONDERN

. J. BENTLEY SQUIER, JR.
. NORBERT STADTMULLER
. M. ALLEN STARR

. RicHARD STEIN

. ANTONIO STELLA

. ABRAM R. STERN

. GeorGE D. STEWART

. Lewis A. STIMSON

. Wimu1AM 8, STONE

. Georce M. Swirt

. PARKER SYMSs

. ALFRED §S. TAYLOR

. JOHN S. THACHER

. ALLEN M. THOMAS

. W. Gruman THOMPSON
. Winuiam H. THomson

PRor.
PRor.
Pro.

ASSOCIATE MEMBERS—Continued.

. SAMUEL W. THURBER

. WisnER R. TOWNSEND

. PHILIP VAN INGEN

. RicHARD VAN SANTVOORD
. JAMES ID. VOORHEES

. Henry F. WALKER

. JOHN B. WALKER

. JOSEPHINE WALTER

. JAMES SEARS WATERMAN

Dr. R. W. WEBSTER

Dr. JOHN E. WEEKS

Dr. Ropert WEIR

Dr. Hersert B. WILCOox

Dr. Linsty R. WILLIAMS
Dr. WILLIAM R. WILLIAMS
Dr. MarGcaret B. WILSON
Dr. GEORGE WOOLSEY

Dr. JOHN VAN Doren YouNG

Dr. Hans ZINSSER

HONORARY MEMBERS, 1912

Pror. J. GrorGeE ADAMI
Pror. Lewetutys F. BARKER
Pror. Francis G. BENEDICT
Pror. T. G. Bropie

Pror. A. CALMETTE

Pror. W. E. CaAstTue
Pror. WALTER B. CANNON
Pror. Hans CHIARI

R. H. CuHrrrenpen
OTto COHNHEIM
W. T. CouncILMAN

Pror. GEorGE W. CRILE
Pror. Harvey CUSHING
Pror. ArtHuR R. CusHny
Pror. Davin L. Epsauu
Pror. W. W. Fata
Pror. Orro Foun

PROF.

Ross G. Harrison

Pror. Lupvicg Hex Torn

PrRor.
Pror.
Pror.

W. H. Howetuu
G. Cart HuBER
JOSEPH JASTROW

Pror. Hersert §. JENNINGS
Pror. Epwin O. JorDAN

Pror.

ALBRECHT KosseL

Pror. Joun B. Leatugs
Pror. A. Macnus-Levy

Pror. JACQUES LOEB

Pror. A. B. MacatLuM
Pror. LAFAYETTE B. MENDEL
Pror. Hans MEYER

Pror. CHARLES §. MINoT
Pror. S. Weir MircHELL
Pror. THomas H. Morcan
Pror. FRIEDRICH VON MULLER
Pror. CARL VON NOORDEN
Pror. FREDERICK G. Novy
Pror.. HENRY FAIRFIELD OSBORN
Dr. THomas B. OSBORNE
Pror. RicHArD M. PEARCE
Pror. WILLIAM T. PORTER
Pror. JAMES J. PuTNAM
Pror. THEODORE W. RICHARDS
Pror. E. A. SCHAEFER

Pror. WILLIAM T. SEDGWICK
Pror. THEOBALD SMITH
Pror, Ernest H. STARLING
Pror. A. E. TAYLOR

Pror. W. S. THAYER

Pror. MAx VERWORN

Pror. J. CLARENCE WEBSTER
Pror. H. Grpron WELLS
Pror. EpmunpD B. WILSON
Sm Autmroto E. WRIGHT

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PREFACE

WHILE the Harvey Society becomes responsible to a larger
audience each year, the prestige and character given to its
undertaking by the generous services of the lecturers makes
the work of arranging for the annual series and the publication
of the volume progressively easier.

The lectures of Dr. Flexner, Prof. Kossel, Prof. Richards,
Prof. Chittenden, and Prof. Thayer have not appeared in
previous publications.

The Editor acknowledges gratefully the courtesy of the
Epitors of the Johns Hopkins Hospital Bulletin, the Boston
Medical and Surgical Journal, the Journal of Infectious Dis-
eases, the Popular Science Monthly, and the American Natu-
ralist, in allowing our republication of the lectures of Prof.
Verworn, Prof. Putnam, Prof. Sedgwick, Prof. Cannon, Prof.
Jennings, and Prof. Osborn respectively.

The Society is indebted to Dr. H. D. Dakin for his trans-
lation of Prof. Kossel’s lecture, which was delivered in German.

HaAvEN EMERSON, Secretary,
120 East 62d St., New York.
September, 1912.

CONTENTS

PAGE
Hecal Specific Therapy of Infections ......... 0s cccccsccccccecs 17
Dr. Smiuon FLEXNER—The Rockefeller Institute for
Medical Research.
The Chemical Composition of the Cell............. ga dhl eee wearer eae 33
Pror. ALBRECHT KosseL—University of Heidelberg.
RRS TENI et fe 8 a Slat wat acl cn a atl wi Sia vatiel Soho wlcletaran oles Crelarene terse oie 8 52
Pror. Max VERwoRN—University of Bonn.
On Freud’s Psycho-Analytic Method and Its Evolution............ 76
Pror. JAMES J. PurnamM—Harvard University.
Illuminating Gas and the Public Health...................000cce. 100

Pror. W. T. SepGwick—Massachusetts Institute of Technology.

A Consideration of the Nature of Hunger.................cccecees 130
Pror. WALTER B. CanNoN—Harvard University.

The Continuous Origin of Certain Unit Characters as Observed by a
MaPUPEIPET HERMES ete ohh chs 92 aol hai) ude gh ef ese aes afte tCoubal Spa Negeo annie e 153

Pror. Henry FarrFieELD OsBorN—Columbia University.

The Relation of Modern Chemistry to Medicine................... 205
Pror. THEODORE WILLIAM RicHarpDs—Harvard University.

Some Current Views Regarding the Nutrition of Man ............. 225
Pror. Russett H. CarrrenpEN—Yale University.

Age, Death, and Conjugation in the Light of Work on Lower Organisms. 256
Pror. H. 8. Jennrnas—Johns Hopkins University.

On Malarial Fever, with Special Reference to Prophylaxis .......... 277
Pror. Witu1AM SypNrEyY THayer—Johns Hopkins University.

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LIST OF ILLUSTRATIONS

PAGE
The top record represents intragastric pressure ; the second record is

time in minutes (ten seconds); the third record report is of

hunger pangs; the lowest record shows respiration............. 146
The same conditions as in Fig. 1. There was a long wait for hunger to
ODE SUSE Sil ene aS OBR ces, vee ene 0 Re Se eee nee 147

The top record represents compression of a thin rubber bag in the
lower cesophagus. The middle line registers time in minutes

(ten seconds). The bottom record is report of hunger pangs... 148
Continuous origin of allometric ‘“‘unit characters’ in the cranium A and

pias on man ang titanouheres ss... 23. 5 oso cea dost cas woticex ss 177
Continuity in the ontogenesis of the horn and horn sheath in cattle in

SOSTABIA (SERCO LE FR RA eee a PCa LE Oe ne Pa Ra 180
Rectigradations and allometrons in titanotheres...................... 184
Continuous origin of allometric ‘‘unit characters” in the skull of various

NMR Nae IAN ve ec SS sal eg aleye eM Se, thy Ge) etere Sroe 187
Cross-breeding and imperfect blending of allometric “unit characters”

of the facial bones in ass (male), horse (female), and mule ...... 190
Cross-breeding and imperfect blending of sub-allometric ‘‘unit charac-

ters’’ of the nasal bones in ass (male) and horse (female)........ 193

Cross-breeding and imperfect separation of allometric ‘‘sub-unit charac-
ters’’ of the nasal bones in ass (male), horse (female), and mule, 195

Cross-breeding and separation of rectigradations, distinct “unit char-
acters’? in the enamel foldings and pattern of the grinding teeth
POMBE Ese PIE ANG SBOPSE!.. ssc 24 «Le oo 40 tie close see oe ad Grates 200

CHARTS

Death rates from measles, scarlet fever and illuminating gas poisoning, 107

Illuminating gas manufactured and deaths from gas poisoning........ 110
Percentage of water gas in total gas made. Deaths by gas poisoning

per billion feet of total gas. Suicides by all methods........... 115
Death rates from illuminating gas poisoning; from suicides by gas;

Ae URAL CNCTNGR YY, GEES 25h \2 Bh yin wlcta 0, ap Diels cd Slaves aba ae Geunieiats 119
Deaths from gas poisoning, deaths from suicide by all methods, and

CRI ER eee ae RS ei ee SU i Naa Wu aftcate me nldiala bles 121

Seasonal distribution of deaths from gas poisoning ................... 123

LOCAL SPECIFIC THERAPY OF
INFECTIONS *

SIMON FLEXNER, M.D.

HE specific treatment of infectious diseases has, as you are
aware, made great progress during the last two decades.
In this time some of the most potent curative agents have been
perfected and introduced into practical medicine. However,
the achievements of an earlier period in this field should not be
minimized. One has merely to allude to the examples of
quinine and mercury, to be reminded of the discovery of two of
the most perfect drugs for the conquest of specific infections
that are still at our disposal. Moreover, these specific remedies
date from a period anterior to the present one, in which new
remedies are worked out in the laboratories before they are
applied to the relief of human suffering. Since the experi-
mental method in medicine is responsible for the recent great
advances that have been made, it will be of some interest to
refer in passing to the circumstance that the discovery of
quinine and mercury was not through magic or intuition but
also by experimentation, but in this instance the experiments
were conducted upon sick human beings. That is to say, the
adoption of these drugs represents merely a selection out
of countless hundreds of substances that had at one time or
another been tested against the diseases malaria and syphilis.
We are to consider briefly the subject of a specific form
of treatment of disease that is distinguished by the peculiarity
that it comes to be applied locally to the focus of infection. —
In order that we may appreciate the purpose of this method,
and also the nature of the method itself, it will be necessary to
lay before you a few general data concerning the subject of
' infection and of recovery from that condition,

* Delivered October 7, 1911.

18 HARVEY SOCIETY

In the pursuit of knowledge of the subject of infection, no
aspect of the problem has been more enlightening and re-
warding than that relating to the reasons for spontaneous re-
covery from infectious disease. The leading physicians have
rarely failed to appreciate the unexcelled power of Nature her-
self to heal her self-inflicted wounds, and to recognize that many
diseases tend of themselves, when not quickly fatal, to progress
toward recovery. There resides, therefore, within the animal
body, a set of potential forces capable, when aroused, of exer-
cising a highly effective control over disease. You are familiar
with the fact that these powers have been traced to a group
of substances contained within the blood and passing from
the blood into the lymph, where they exert influence on the
cells composing the organs and on parasites in the interstices of
their tissues.1 What these substances consist of has already
been ascertained in good part, so that they may be classed
briefly into soluble, complex chemical bodies, probably of
protein nature, that are contained dissolved in the fluids, and
of certain mobile white cells, the so-called leucocytes or phago-
eytes. In virtue of the soluble form and the motility of the
cells, these healing substances are able to reach most parts
of the body where their special properties may be exerted.
Moreover, not only are these curative substances, technically
called ‘‘immunity principles,’’ preformed in all individuals
in which they operate against intending infection, but they

*The native curative powers of the blood have been invoked to
heal local diseases through the creation of a condition of artificial
hyperemia or congestion. “All organs that functionate are hyperemic
during activity. In every form of growth and regeneration local
hyperemia is present and in a degree corresponding to the rapidity
and energy of the growth..... All reactions to foreign substances,
whether erude bodies or minute parasites or their chemical products,
are associated with hyperemia. There is no lesion which the body
tries to and is capable of removing by rendering harmless, that pro-
duces anemia. Hence if we accept the reactions of the body as
useful efforts of Nature, we must admit that hyperemia is the most
common of all autocurative agents” (Bier, Hyperemia, Translation
by G. A. Bleek).

LOCAL SPECIFIC THERAPY OF INFECTIONS 19

become quickly increased in amount when an infection has
been established; and the ultimate issue of the condition in
spontaneous recovery or the reverse depends upon the degree
of this response to infection and the competency of the cura-
tive principles evoked to reach and to suppress the infectious
agent.

These principles come to operate equally against all classes
of microbic parasites, whether protozoa, bacteria, or that re-
markable class the import of which we are just learning—
the so-called submicroscopie or filterable organisms or viruses.”
But the effectiveness of their operation is determined not only
by the intrinsic qualities of parasite and of host, but also in a
high degree by the manner of location and distribution of the
parasites themselves within the infected host. Whether they
have a general distribution throughout the blood and tissues
or whether they are confined within a pathological process
in the interior of an important organ or part, may be the
factor determining whether not only the native curative prin-
ciples shall gain ready access to them, but whether also ex-
traneous curative agents introduced into the body shall be able
to reach the seat of disease.

The parasite, struggling to survive, withdraws, at one time,

*A number of diseases of the higher animals, including man, and
one disease of plants (the mosaic disease of tobacco) have, within
ten years, been traced to submicroscopic parasites. It is indeed not
remarkable that the present microscopes should have failed to define
the limits of organized nature. Whether we shall ever invent instru-
ments capable of resolving and rendering visible these minute
particles of living matter is a question impossible to answer. Even
doubling the potential power of the microscope by the device of
employing, for photographie purposes, the ultraviolet rays of the
spectrum has failed to bring them into view. Their place in nature
is not accurately established. Some, as the parasite causing yellow
fever, that passes a stage of its existence in mosquitoes, probably
are protozoal; others, as the parasite of pleuropneumonia of cattle,
that can be propagated in artificial cultures, probably are bacterial.
It can hardly be doubted that they are living organisms, since they
are capable of transmission from animal to animal, in which they
produce infection, through an indefinite series.

20 HARVEY SOCIETY

into situations to which the curative substances gain access
imperfectly and with difficulty, causing thereby local infee-
tions more or less cut off from the general circulation and the
curative agents purveyed by the blood. This is the condition
met with in massive inflanimations, in abscess formation, and
in infections of specialized portions of the body—such as the
ereat serous cavities—that receive normally a modified and
dilute lymph secretion.

It is the lymph that carries the protective as it does the
nutritive principles for the tissues and organs; and hence this
fluid provides the essential safeguard against infection. More-
over, the quality of lymph in the several serous cavities is not
the same, but is, indeed, peculiar for each cavity, and the
lowest limit of strength is reached by the cerebrospinal fluid
—regarded as the lymph of the brain and spinal cord, which
is almost devoid of protein matter.2 As the protein moiety
of the lymph carries the immunity principles, it follows that
the serous cavities are really less well supplied with them, and
the subarachnoid space of the central nervous system the least
well of all. These considerations are not without high im-
portance as affecting the provisions for warding off intending
infection, and especially for controlling and abating an estab-
lished infection. Since the anatomical structure decides the
quality of the lymphatic fluid in health, it also determines it

*The notion that the cerebrospinal fluid is the lymph of the
central nervous system is open to discussion. Mott (The Lancet,
1910) suggests that it “may serve as the ambient fluid of the neurons
and play the part of lymph to the central nervous system.” The
fluid arises from the choroid plexus and escaping from the foramina
of Magendie and Luschka into the subarachnoid spaces occupies them
all and communicates, probably, with a “canalicular system surround-
ing the cells and vessels of the brain” (Mott). Thus this fluid should
provide the most direct path for the penetration of active substances
to the nervous tissues; and in fact it has been established by experi-
ment that chemical bodies act upon the nerve eells with greater
energy and certainty when introduced directly into the cerebrospinal
fluid. The hen, indeed, is not subject to the effects of tetanus toxin
injected into the blood, while it suffers from tetanus when it is in-
jected into the subarachnoid spaces (Behring).

LOCAL SPECIFIC THERAPY OF INFECTIONS 21

in disease, and thus by regulating the composition of this fluid
commands the issue of the pathological process. Under such
circumstances the parasite that becomes localized in these
cavities is insured a potential advantage against the host.

The parasites possess, moreover, an advantage of regulation
within themselves to preserve them from extinction—they are
capable of altering rapidly, not their form and external ap-
pearances, but their chemical reactions and probably chemical
structure when too closely pressed and menaced. The change
consists in the development of a state of effective resistance,
called ‘‘ fastness,’’ to injurious chemical agents, whether the
immunity principles of the blood or other substances. The
new qualities acquired have been viewed as the result of muta-
tion among the parasites, and the mutants have been observed
to transmit the new characters through an indefinite number
of generations. It is precisely this property of mutation that
we are learning to hold accountable for the troublesome or
dangerous relapses that occur in many of the parasitic diseases,
commonly for example in malaria, sleeping sickness, spiro-
cheetal infection, to mention only a few.* Finally, the so-called
chronic carrier of infectious organisms, who is being recognized
as a serious menace to the health of society and is sincerely to
be pitied, is to be regarded often as the victim of this form of
mutation among the micro-organisms which at one time caused
him to be ill, but to which he, but not his fellows, has become
adapted. In the successful exploitation of specific thera-
peutic measures account must obviously be taken of the biologi-

*This parasitic mutation or “fastness” is more readily developed
against serum immunity principles (antibodies) than against chemical
agents of the nature of drugs, but once produced, the latter effect is
the more difficult to remove. Serum fastness may be overcome by
the superinfection of an animal that has recovered from infection
with the corresponding “fast” strain, through which reversion to the
normal type may be accomplished; while chemical mutation is over-
come solely, apparently, through sexual conjugation of protozoal
parasites in the body of an appropriate insect host (Ehrlich, Folia
Serologica, 1911, p. 697).

22 HARVEY SOCIETY

cal conditions described as well as others that may in time be
discovered.

Manifestly, therefore, the bringing of the parasitic causes
of microbic diseases under the influence of curative agents will
be more readily and certainly accomplished when they are
widely disseminated throughout the body than when they
are hidden away within an organ or in the interior of a serous
cavity. Hitherto the most effective agents of specific treat-
ment have been just those that operated against the general-
ized infections, of which examples are such drugs as quinine
in its action against the malarial parasite, and mercury in its
effect on the spirochxtal cause of lues. The same result is now
being achieved by salvarsan, recently discovered by Ehrlich,
in respect to its application to a number of spirochetal affec-
tions in man and the domestic animals; while the control of
diphtheria by antitoxin, perhaps the most perfect example of
all, consists essentially in the neutralization of a universally
distributed toxic or poisonous agent that is directly the cause
of the serious effects of the disease. When, in generalized
infections, the surviving micro-organisms escape from the blood
and tissues, as sometimes happens in luetic or other diseases,
to aggregate in special situations and local pathological products
that are reached imperfectly by the lymph, then the specific
drug or other agents assert: their curative powers with far
more difficulty and far less certainty.

Medicine is now armed with a number of specific remedies
for serious diseases, consisting partly of chemical compounds
of known composition and partly of more complex serum
products of unascertained nature. The number of drugs is
potentially greater than the number of sera and is capable of
almost unlimited expansion, so that doubtless therapeuties will
be greatly enriched by future discovery in this fascinating field.
That many immume sera are capable of being prepared artifi-
cially is also certain, but the degree of their applicability will
need to be worked out in any given instance. It is already clear
that the immune sera closely resemble the natural defences
against infection and its consequences, so that it follows that

LOCAL SPECIFIC THERAPY OF INFECTIONS 23

they are essentially non-foreign bodies, and thus, technically,
ideal agents with which to combat disease. They are, in
essence, so precisely fashioned as to operate exclusively against
the agents of infection, and thus to pass over without molesta-
tion the sensitive cells of the organs. In fact, their action is
less specific than this statement implies, because, as now manu-
factured, they carry with them in the natural serum of animals
certain alien substances that do effect, in some degree, the host
himself. A factor that bears upon the production of curative
immune sera as well as upon specific drugs is that of fastness
or mutation of the micro-organisms within the body. Experi-
ment has already disclosed the high importance of- this un-
expected phenomenon of infection. In the choice of especially
fashioned drugs the two properties that now determine avail-
ability for practical medical employment are, first, a low degree
of toxicity for the organs of the host, and second, absence of
the tendency to produce fast strains of the parasite upon which
they exert their influence.

We have still to learn the extent to which specific drug
treatment of the infections is capable of altering the state of
the acquired immunity to infectious diseases that protects, in
some instances, from second attacks of maladies. Important
facts bearing on this subject are already appearing in connec-
tion with the more energetic modes of treatment recently intro-
duced for the spirochetal infections. It seems that possibly the
refractory state in these infections is the result of an enduring
sub-infection, the complete removal of which exposes the
individual to reinfection.’ In a similar manner it would appear
that in the suppression of microbie agents of disease by the
body’s forces through a process of immunization, the serum
products are more varied and complex than are produced in the

*Ehrlich (loe. cit.) explains this phenomenon in a slightly but
not fundamentally different manner. He accounts for the decreasing
number of spirochete, as the disease advances, by a wiping out of
the parasites through the action of the successive specifie antibodies
formed. The fresh outbreaks or relapses, then, are caused by mutants
or fast strains that are immune to the antibodies thus far elaborated,

24 HARVEY SOCIETY

course of artificial immunization of animals that are destined
to yield sera to be employed passively, by injection, in the
treatment of their corresponding diseases; and that this greater
complexity arises from the circumstance that in the suppression
of the micro-organisms in the infected body, not only the normal
strains but also the mutants are successively overcome, with
the result that a series of immune principles, each directed
against its particular variety of parasite, is elaborated.
Diseases of a relapsing character are accountable for on the
basis of the conception that each successive relapse coincides
with the appearance of a new mutant of the infecting organism ;
and the typical disease of this class, relapsing fever, so-called,
is characterized by the ability of its spirochetal cause to under-
go at most three or four mutations that in turn lead to an equal
number of relapses, which, if survived, are followed by an
enduring disappearance of the infection. Hence in the arti-
ficial production of curative sera we shall have to take account
of the mutants or fast strains of the micro-organisms used for
immunization purposes. This result is not necessarily accom-
plished, although it may be promoted by selecting cultures
from many. different sources. What is required is that we
shall learn to distinguish the fast strains or mutants outside
the body in cultures and even, indeed, to create them at will
so that they may be employed for enriching the sera produced
in animals that will thus be better adapted to their purpose of
suppressing the parasitic causes of disease.

The successful issue of specific therapeutics, toward which
goal our hopes have been eagerly turned by the triumph of
experimental medicine, will be secured not only by the pro-
duction of more perfect instruments for the suppression of the
microbie causes of disease, but also through a more effective

and the subsidence of the lesions depends on the production of anti-
bodies for the new strain. During the actual existence of the syphi-
litie infection insusceptibility to reinfection is secured by the presence
of antibodies in the blood to which the strain of spirocheetee, intend-
ing to infect, is not immune. But once the disease is actually
terminated and all the antibodies have been discharged, reinfection
with a normal strain becomes possible.

LOCAL SPECIFIC THERAPY OF INFECTIONS 25

application of the curative agents themselves to the seat of
disease.

I have alluded to the circumstance that the infectious agent
may be strengthened in its attack by confinement within the
organism, through which confinement it is preserved from
injury by the defensive principles in the blood and lymph.
Now no group of infections is in position better to secure this
protection than that located within the membranes surrounding
the brain and spinal cord, the fluid contents of which are so
poor in defensive principles; and for this reason, and for the
reason also that the subarachnoid spaces in these membranes
are in such intimate association with the peri-cellular spaces
about the sensitive nerve-cells, the consequences of meningeal
infections are highly serious. To endeavor to reach the infec-
tions seated in the membranes by means of the general blood
and lymph circulation is futile because of the established fact
that not only are the large protein molecules, which include
the immunity principles, not secreted within the membranes,
but also because highly diffusible salts tend as well to be
excluded. But what cannot be thus accomplished by indirec-
tion can, in this important instance, be achieved by direction.
No operation is simpler in competent hands than lumbar
puncture, so-called, which came into use originally to provide
cerebrospinal fiuid for purposes of diagnosis and now promises
to be of far greater value in affording the means of local
specific treatment of meningeal infections. How valuable this
route may be for the introduction of curative agents is illus-
trated best at the moment, perhaps, by the convincing results
that have been obtained in the treatment of epidemic cerebro-
spinal meningitis by the antimeningitis serum. This thera-
peutic agent is utterly without effect on the local infection when
introduced directly or indirectly into the blood, but it has
proven of unmistakable value when injected into the seat of
the disease by lumbar puncture. The latest figures relating
to its employment are, and should be, the most favorable to
its action, since the methods of production and administration
have been improved through experience; and, therefore, it is

26 HARVEY SOCIETY

a source of gratification that in the recent French epidemic
of meningitis the gross mortality among cases treated by serum
injections begun in the first three days of illness fell below
10 per cent.

The results secured in epidemic meningitis have suggested
the extension of the method of direct local specific treatment to
still other kinds of infection of the meninges. Meningitis is
now known to be caused by a number of micro-organisms, in-
eluding the streptococcus, staphylococcus, pneumococcus, the
bacillus of tuberculosis and of influenza. Generally speaking,
all these inflammations are highly fatal in character, There
is still doubt whether recovery from tuberculous meningitis
ever takes place; the number of recoveries from pneumococcus
meningitis is surely very few; and while we are just learning
the extent to which influenzal meningitis prevails, we can
already predict that the infection is not only not infrequent,
but it is highly fatal in character. Many cultures of influenza
bacilli have slight or non-appreciable action on animals, and
cannot, therefore, be employed for purposes of artificial
immunization; but cultures obtained from cases of influenzal
meningitis not only can be used for preparing an immune
serum, but also produce, when injected into monkeys, a form
of meningitis that in its nature, course, and fatal effects can-
not be distinguished from the spontaneous human affection.
This experimental fatal disease, like epidemic meningitis, can
be controlled by the intraspinal injection of an anti-influenzal
serum. The degree of applicability of this serum to the treat-
ment of spontaneous disease in human beings is still to be deter-
mined; but in view of its highly fatal character it should be
tried. Undoubtedly, it will be necessary to apply the serum
early and by repeated injection to secure beneficial results;
and the early application will be dependent upon prompt
bacteriological diagnosis, which can be made by immediate
microscopical examination of the cerebrospinal fluid.®

Influenzal meningitis, as it oceurs spontaneously or is pro-
duced exper imentally, | is attended by an invasion of the blood

*See Wollstein: Jour. Exp. Med., nea xiv, p. 73.

LOCAL SPECIFIC THERAPY OF INFECTIONS 27

with the influenza bacilli which sometimes appear there in
large numbers. It is important, therefore, to consider the conse-
quences of the bacteremia, as it is called, upon the local treat-
ment of the meningeal infection. Now, fortunately, the diffi-
culties surrounding the passage of the antiserum from the
blood into the cerebrospinal fluid are sharply contrasted with
the ease with which the antiserum escapes from the meninges
into the blood. This discrepancy is explained by the fact that
while the fluid on entry is in the nature of a secretion from
the choroid plexus, the escape is by way of the veins in the
membranes themselves.

While, therefore, it is impractical to bring the antiserum
into the meninges from the blood, the reverse effect is readily
accomplished ; and thus it comes about that in such secondary
infections of the circulation with bacteria as are being here con-
sidered, the suppression of the local development not only stops
the eruption of bacilli that causes the blood infection, but the
passage of the antiserum from the membranes into the blood
arrests their development there.

Probably recovery from any local bacterial infection is not
wholly accounted for by the several activities of blood-serum
and phagocytes that are usually invoked to account for the
phenomenon. This restricted view leaves out of consideration
certain definite chemical substances that are always present in
a focus in which tissues and cells are disintegrating. That
some of these substances are injurious to bacteria we now know.
While the nature of the so-called stabile bacterial substances
yielded by extraction of the somatic cells is still doubtful, it
would appear that among them are certain soaps yielded by
disintegration of the neutral and higher phosphorized fats con-
tained within protoplasm. That soaps are injurious to bacteria
has been abundantly proven; so that the view should be enter-
tained that the degeneration of leucocytes and tissues which
results from a local bacterial infection may not be entirely to
the advantage of the parasitic agent, but is also of use to the
body in assisting it to overcome the bacteria, since the cells
brought to death and disintegration by the parasites yield

28 HARVEY SOCIETY

chemical substances that themselves exert a destructive action
upon the infecting bacteria.

The application of these considerations to the treatment of
a typical pneumococcus infection, such as the experimentally
produced pneumococcus meningitis in the monkey, has been
rewarded with significant results. We are still ill-informed of
the factors which control resistance to and recovery from a
local pneumococcus infection. The decrease in number of the
organisms that takes place as recovery progresses in lobar
pneumonia, for example, has not been shown to depend either
on phagocytosis or on serum solution of the bacteria. It is a
highly suggestive fact that the pneumococcus differs from most
bacteria by reason of its solubility in chemical solutions, such
as those containing bile-acids and, as has been recently discov-
ered, soaps. The effect of soap is peculiar in that exposure
of the pneumococci to its weak action merely modifies the
texture without altering the growing properties in cultures,
so that when the soaped pneumococci are next exposed to
blood and serum, and especially to an antipneumococeus serum,
they suffer complete dissolution. These conditions are, indeed,
present in a local pneumococcus infection since soaps are pro-
duced there, and during its progress immunity aa appear
in the blood and lymph.’

By employing a suitable combination of sodium oleate and
antipneumococeus serum, experimental pneumococcus infections
of the meninges can be controlled and abolished. Through
this means monkeys that would surely have succumbed have
been repeatedly restored to health. But the successful employ-
ment of the soap and serum mixture rests upon the overcoming
of the property that the soap possesses of uniting with the
protein of the antiserum and thus being rendered inert and
withheld from acting upon the pneumococeus. This obstacle
is the common one on which so many high hopes of the chemical
suppression of infections, by. what is termed ‘‘internal anti-
sepsis,’’? have been wrecked. Luckily, in this instance, it has
been proven that the soap portion can be kept apart from the

ie See Lamar: Jour. Exp. Med., 1911, xiii, p. 1.

LOCAL SPECIFIC THERAPY OF INFECTIONS 29

protein moiety of the serum by introducing a second protective
chemical body, itself innocuous, into the mixture. When minute
quantities of boric acid are thus introduced, the soap is isolated
and left in condition to exert its injurious action upon the
pneumococci, for which organisms it appears to have a greater
affinity than for ordinary protein matter. Whether among the
products of local tissue disintegration a similar separation of
the soap and serum elements is secured has not been ascer-
tained; but we should consider factors that possibly suffice to
overcome this initial impediment to the bactericidal action of
the soaps, among which are the proximity of the bacteria to
the nascent fatty acids and soaps and the natural occurrence
within the exudate of chemical bodies that have the effect
of removing the protein inhibition.®

The antisera and the chemical disintegration products of
cells do not exhaust the list of defensive agents that operate
against infection, for there remain the living leucocytes them-
selves. Certain bacterial infections that have not thus far been
made to respond to the dissolved immunity principles may still
be subject to influence by the white cells of the blood. Hence
the effort has been made, and with an encouraging degree of
success, to control experimentally produced tuberculous
pleurisy in the dog by the repeated injection of living leuco-
eytes ;° and the observation made upon this condition has been
extended to include experimental tubercular meningitis pro-
duced likewise in the dog, the course of which it has also been
found possible to affect in a favorable manner.’° In the
pneumococeus and tubercular infections just considered, as in
the influenzal bacillus affection already mentioned, the general
infection of the blood and organs has been suppressed or much
reduced by the local specific treatment.

*The fatty acids and soaps are yielded by the dissolution of the
neutral and the higher phosphorized fats contained within the cellular
protoplasm in which other colloidal bodies of a protecting nature
may well be stored.

*See Opie: Jour. Exp. Med., 1908, x, p. 419.

‘® See Manwaring: idem, 1912, p. 1.

30 HARVEY SOCIETY

Although the treatment of these tuberculous affections with
leucocytes is still in the experimental stage and is not yet ready
for application to medical practice, it has been described in this
connection in order that there might be brought under review
the diverse means that are at present invocable in the efforts to
determine the conditions that underlie the therapeutic control
of varied infectious processes.

Finally, the application of the principle of the local treat-
ment of infections holds out hope of some measure of thera-
peutic control, at least, of that serious and menacing disease,
now in the foreground of interest for physicians and public
alike, namely, epidemic poliomyelitis. The propagation of the
disease in monkeys has led to the elucidation of its cause and
pathology, while at the same time it has exposed it to thera-
peutic experimentation. The cause of the malady is an exceed-
ingly minute parasite—submicroscopie and _ filterable—which
probably gains access to the spinal cord and brain by way of
the meninges and through the lymphatic connections that sur-
round the olfactory filaments that terminate in the nasal
mucosa and are in direct communication with the subarachnoid
spaces. The lesions of the meninges constitute an important
effect of the infection, and especially of those prolongations
of the meninges about the veins and arteries that enter the
spinal cord and bulb and support the perivascular lymphaties.
The lymphatics and, indeed, the subarachnoid spaces in general,
comprise a system of communicating channels charged with
cerebrospinal fluid that extend to the pericellular spaces and
therefore penetrate to the nerve-cells. Consequently a para-
sitic or toxic agent that gains access to the cerebrospinal fluid
is capable of ready transportation to all parts of the nervous
system; and by utilizing the same route it is obviously possible
to distribute what may prove to be a soluble antagonistic and
therapeutie agent.

Recent experiments have shown unmistakably that spon-
taneous recovery from poliomyelitis is brought about by a
set of immunity reactions that involve the formation in the
blood of soluble principles or antibodies for the parasitic

LOCAL SPECIFIC THERAPY OF INFECTIONS 31

virus. Similar principles are formed in inoculated monkeys;
and they can be used successfully, up to a certain point, when
injected into the spinal canal by lumbar puncture, in preventing
the development, after an intracerebral inoculation of the virus,
of experimental poliomyelitis. This effect has not yet been
accomplished by the introduction of large quantities of immune
blood into the circulation, a result that was predictable in view
of the location of the pathological process that leads to the
paralysis in the meninges.

It is not excluded that epidemic poliomyelitis may be sub-
ject to effective treatment by drugs. There is, indeed, one
drug—urotropin, or hexamethylenamin—that does exert some
action even when administered by the mouth, since it presents
the exceptional instance of a chemical body being excreted into
the cerebrospinal fiuid.1t But its powers are limited. How-
ever, as the drug is constituted in a manner that permits of
many modifications of its composition without the sacrifice of
its central structure through which formaldehyde may be
liberated, it has been found readily possible to prepare a
number of derivatives far exceeding urotropin in activity,
some of which have been applied to the treatment of experi-
mental poliomyelitis with a hopeful measure of success. These
new compounds, it should be added, require to be injected into
the spinal membranes and act best in conjunction with an
immune serum.??. They are subject to rapid dissociation, upon
which phenomenon probably their high activity depends; and

*See Crowe: Bull. Johns Hopkins Hosp., 1909, xx, p. 102.

“The advantage to be secured against the parasites by employing
more than one antagonistic agent results, first, from the circumstance
that an antibody or drug will operate with greater effect against an
already injured than against a normal parasite, and secénd, because
mutation in two directions is less readily effected than in one direction.
Hence a fortunate combination of serum antibodies and a drug
offers, theoretically, a favorable means of overcoming an infecting
micro-organism. Ehrlich (loc. cit.) recommends the simultaneous
employment of two curative substances, one of which is especially
chosen to injure the protoplasm and the other the nuclei of the
parasites.

32 HARVEY SOCIETY

the dissociation proceeds somewhat more slowly in the presence
of the colloidal constituents of the immune serum that itself
carries a small amount of healing substances. This is obviously
no more than a beginning in the effort to accomplish thera-
peutic control of this protean and serious disease, the natural
history and significance of which are just beginning to be
appreciated ; but the outlook for its conquest is at the moment
made hopeful through the utilization of the method of the local
specific treatment of infections.

The arguments that have been presented and the examples
adduced would seem to possess not only theoretical but also
established value in justifying the further pursuit of the
measure of opposing local infection by local specific remedies.
In the effort to combat the infectious processes account will
have to be taken, in any given instance, of the peculiarities of
the infecting parasite, as well as the particular anatomical and
physiological adjustments of the infected parts, that together
constitute the foundation upon which effective specific thera-
peutic effort must ultimately come to rest.

THE CHEMICAL COMPOSITION OF
THE CELL*

PROFESSOR ALBRECHT KOSSEL
Physiological Institute, Heidelberg

HEN, in response to your President’s invitation, I at-

tempt to put before you a bird’s-eye view of some of
the problems which are occupying the attention of biochemists
at the present time, I am very cognizant of the difficulties of
my task. The anatomist, the pathologist, and the clinician can
present his observations to you directly, but this is not possible
for the chemist. ‘The phenomena which the chemist studies are
only intelligible when considered with the help of a special
nomenclature, based upon chemical theories. His results are
expressed in a special language in which the letters of the
alphabet are represented by elements, the words by chemical
formule. He makes use of theoretical conceptions when he as-
sumes certain spatial relations for atoms and molecules that
we can neither see nor feel. He discusses the arrangement in
space of things which are inaccessible to our direct observation.
These peculiarities make the presentation of his results specially
difficult.

When, notwithstanding, I draw your attention to these lines
of investigation, it is with the profound conviction of their
great importance. It may be truly said that to-day the eyes
of the biologist and the pathologist are directed hopefully to-
ward chemistry. Everyone who is engaged upon the investiga-
tion of the processes of life in the cell, with the problems of
fertilization, or of contractility, with the phenomena of nutri-
tion, respiration, or growth, comes to the conclusion that all
these manifestations of life are ultimately to be referred to
chemical changes, and it is chemistry that must bring us the

* Delivered October 14, 1911.
3 33

34 HARVEY SOCIETY

solution of the most important of the mysteries of life which
are accessible to investigation. When we consider the extra-
ordinary results of chemistry obtained during the last century,
we may well be inclined to expect even more wonderful re-
sults in the future, but it is certain that they cannot be obtained
at once. It requires long and intensive work to develop from
the elementary chemistry of to-day a higher chemical science
capable of analyzing those complex chemical processes which to-
gether constitute life.

To-day we are concerned with the question as to how far
chemistry has been of service in promoting our knowledge of
the processes of life. How may chemistry concern itself with
the fundamental questions of physiology? What are the bio-
chemical problems which we may successfully attack in the
present state of our knowledge? The medical student begins
his studies with anatomy, and the biochemist who investigates
the finest details of metabolic changes must begin in a similar
fashion. First of all, he must concern himself with questions
relating to the presence, distribution, and properties of certain
chemical constituents of the animal body. Only when this has
been accomplished is it possible for him to approach the chem-
ical processes taking place between these different constituents,
which together form the basis of metabolic changes.

Moreover, the chemical consideration of the various sub-
stances present in the body resembles anatomical studies in that
both of them are concerned with spatial relationships. I have
already referred to the fact that we think of the atoms as ar-
ranged in definite positions in space. These arrangements of
the atoms, which together make up the ‘‘ formula,’’ give to the
chemist a presentation of the properties of a substance. When
we have obtained such a formula, we can predict to a certain
extent how a substance will behave in certain chemical reac-
tions and with certain chemical reagents, and also its behavior
toward the chemical actions which are operative in the living
organism. If, for example, we find in a chemical formula the
group COOH, we infer that the substance possesses the prop-
erty of an acid, while the group NH, is indicative of basic
qualities. We learn also whether it is attacked by oxygen with

CHEMICAL COMPOSITION OF THE CELL — 35

ease or with difficulty, and whether its decomposition by one or
other ferment is probable. Thus the foundation for our bio-
chemical considerations is derived from chemical formule, just
in the same way as physiological and pathological considerations
are derived from anatomical representations.

I should like to carry the comparison between anatomical
and biochemical investigations still further. Laws governing
the anatomical relationships of the human body and also the
sciences of pathology and physiology have entered upon a new
era, since it has been possible to determine certain cellular
units in plant and animal tissues which act as centres for de-
velopment, for nutrition, and for numerous other special func-
tions. Through the determination of these units it has been
possible to define more exactly many physiological and patho-
logical processes, and also to compare them with one another
and so make them more intelligible.

Biochemical investigations require the consideration of
similar units. So long as one considers the mass of living
substance as a whole, an analysis of its activity ean scarcely be
undertaken. Such an analysis is only possible through the
isolation of certain units capable of chemical investigation and
to whose activity the individual functions of living substances
may be referred. I wish to speak of these units, which I shall
refer to as the ‘‘ Bausteine ’’ or building-stones of protoplasm.

The word ‘‘ Baustein ’’ indicates that these units may be
united to form larger structures and that their union takes
place according to a determined plan or architectural idea.
Through the union of these Bausteine larger aggregates are
formed which we call either proteins, fats, nucleic acids, phos-
phatides, or polysaccharides, as the case may be.

On the other hand Bausteine are not the smallest units of
the living tissue, for they are themselves composed of a certain
number of atoms of different kinds, commonly of carbon, hydro-
gen, nitrogen, oxygen, or sulphur. They are, however, not only
anatomical or structural units but also physiological units.

If we wish to obtain a clear picture of the chemical changes
occurring in living substances, we must study the behavior of
these Bausteine. It is with them that we must work in our

36 HARVEY SOCIETY

studies of physiological combustion and of all the processes
bound up with the production and destruction of organic sub-
stances in the animal eells.

In one relation my choice of the term Baustein is not appli-
eable. The Bausteine or building-stones of a house are uni-
form, but the Bausteine of living substances possess a great
diversity. They differ among themselves as much as the stones
of a colored mosaic, and in addition, they are of different sizes.
At times, however, we find aggregates which are formed by the
repeated combination of a single type of Baustein, but in gen-
eral the most varied types of Bausteine are intermingled ac-
cording to a definite plan.

We may ask ourselves what are the reasons for ascribing
to these atomie groups which I term Bausteine a certain indi-
viduality, and for singling them out as units from the more
complex aggregates of atomic compounds which we find in liv-
ing substance. he conception of these atomic groups as
Bausteine is due to their internal stability and also to the
coherence of the carbon atoms which makes them relatively
stable in metabolism. The carbon atoms which go toward the
building up of the Bausteine are arranged either in the form
of chains or of rings. Where one Baustein is united to another
we find another atom such as oxygen, nitrogen, or sulphur
taking part in the union. These latter elements may be re-
garded in a sense as the mortar of the Bausteine. In the fol-
lowing diagram I try to make this clear.

(4) C-C-C-S~-S-C-C-C

CHEMICAL COMPOSITION OF THE CELL 37

The above representation is intended to convey the mode of
union of two Bausteine with one another, and the binding atoms
are indicated in heavier type. One must remember that the
scaffolding or ‘‘ carbon-skeleton ”’ of the Bausteine may greatly
vary in size. The union of two Bausteine, each containing six
carbon atoms, is shown in the first example, while in the second
a Baustein with only one carbon atom is united with one con-
taining five carbon atoms, while the third formula represents
a Baustein possessing a skeleton of nine carbon atoms partly
arranged in the form of a ring united with a side-chain of three
carbon atoms. Finally, in the fourth formula, we have two
chains each containing three carbon atoms. The union of the
Bausteine in the first case is effected by an oxygen atom, in the
second and third, by a nitrogen atom, and in the last case by
means of two sulphur atoms.

We have here four characteristic types of combination such
as are to be found in every living part of animal and vegetable
organisms. It is possible for a much greater number of Bau-
steine to be united in a similar fashion, so that aggregates may
be formed containing several hundred carbon atoms. The reso-
lution of such large structures can be relatively easily accom-
plished at the places indicated in heavy type. This change is
brought about especially by the ferments present in the animal
and vegetable organisms.

Our food contains principally Bausteine united in large
aggregates and not in the form of single units. Through the
secretion of the salivary glands, stomach, pancreas, and intes-
tine, these combinations are to a large extent completely re-
solved, and when necessary their disintegration may be made
more complete by other ferments present in the tissues. But
on the other hand, these large structures may be equally readily
built up from the individual Bausteine. The union of Bau-
steine, ‘‘ the building-up,’’ requires the expenditure of a very
small amount of energy, as is also the case with their decompo-
sition, ‘‘ their break-down,’’ which leads to a very slight libera-
tion of energy.

In addition to these Bausteine, composed of directly united

38 HARVEY SOCIETY

carbon atoms, we have a second form in which the carbon atoms
are not directly united. This is made clear in the following
formule :

TaBLeE II
I II
N-C
Avi ZN-G
C C-Ny - |
ir ee ine? N-C

According to what has been previously stated, Formula I
shows us three different Bausteine, since the union of the carbon
atoms is interrupted at three different places by nitrogen atoms.
In Formula II we might assume the presence of two Bausteine.
As a matter of fact I prefer in both cases to consider the whole
group as a single Baustein, for by the closing of the ring the
union of the atoms is made so firm that they possess marked
resistance to the decompositions of the organism and the whole
system reacts as a unit both within and without the living or-
ganism. I found the first grouping as a characteristic constitu-
ent of cell nuclei. It is also found, however, in uric acid, and
since we find it in the urine, we may regard this as proof of the
stability of this ring-system. The substance whose atomic link-
ing is represented in Formula II was found by me in the pro-
teins and is known as histidine.

I have just spoken of the multiplicity of these Bausteine
and illustrated it with different formule. The variety is so
great that it is necessary for us to limit ourselves for the present
to the more important types. Our choice has, however, certain
restrictions. We find that certain individual Bausteine are
present in all living cells capable of developing, and these re-
eur in unchanged or but slightly changed form throughout the
animal and vegetable world. We ascribe to these Bausteine a
fundamental biological importance, in contrast to others which
occur only in certain orders or families, or possibly only in in-
dividual species.

So far we have only considered the carbon skeleton, which
is contained in these substances; their real character is de-

CHEMICAL COMPOSITION OF THE CELL 39

_ pendent upon other atoms which are attached to this scaffolding
of carbon. In the foregoing tables only the carbon atoms have
been inserted, while further on we shall find that the printed
formule have their skeletons to a certain extent provided so
to say with flesh and blood. By the attachment of oxygen
and hydrogen atoms to a chain of three, five, or six carbon
atoms, substances are formed which are known as polyatomic
alcohols. By the addition of oxygen in a somewhat different
manner we obtain saccharides, the biological importance of
which is recognized by everyone. By the accumulation of oxy-
gen at a particular point in the molecule, the whole complex
assumes acid properties, and in this way the organic acids are
formed, the higher members of the series being found as Bau-
steine of all living cells. As examples of these substances I
may mention butyric, palmitic, stearic, and oleic acids. I
have already mentioned the fact that the union of nitrogen
and hydrogen atoms gives us the amino group, and this, when
attached to a carbon scaffolding, confers basic properties upon
it. Basic Bausteine of this kind can as a matter of fact be
found in all parts of the living organism. As an example we
may mention the amidine group which may be converted into
urea through the entrance of oxygen and hydrogen. The
amino-acids form a group possessing a very wide distribution
and apparently concerned with most important biochemical
functions. The amino-acids possess at the same time the prop-
erties of both acids and bases. A glance at the following
table shows us that they contain both the carboxyl and amino
groups.

The number of amino-acids which are found in protoplasm
is very considerable. They form a series constructed according
to a common plan, and are known as homologous substances.
The simplest member of this group is amino-acetie acid or gly-
cocoll. If we replace a hydrogen atom of glycocoll by the
group CH,, we obtain another substance which is known as
alanine, and this body possesses special interest.

There are many Bausteine which may be regarded as ala-
nine derivatives. All of these derivatives may be regarded as

40 HARVEY SOCIETY

formed by the substitution of hydrogen atoms. Serine for
example, by the entrance of (OH), cysteine, by the introduc-
tion of (SH). If the group C,H;, the so-called phenyl group,
is introduced, we obtain phenylalanine, while the oxyphenyl
group leads to tyrosine. Other groups, such as ‘‘ indol’”’ and
‘“iminazol’’ as substituents of alanine, lead to the formation
of tryptophane and histidine respectively.

Tase III
CH, CH,OH CH,SH CH,-CsH; CH,-CsH,OH
CHNH, CHNH, CHNH, CHN H, CHNH,
Coon Coo COOH COOH COOH

Alanine Serine Cysteine Phenyl- Tyrosine
alanine
CH— NH
CH | CH

ecaire as TG Nea Chee — 4
| |
CHNH,CH C CH CHNH,

| CARA |
COOH NH CH COOH
Tryptophane Histine

It is thus seen that we have a large number of Bausteine
which resemble each other in general structure but which ap-
parently subserve different physiological functions.

The two last-mentioned substances, tryptophane and histi-
dine, both of which contain five carbon atoms directly united
with each other, form a connecting link with those amino-acids
containing more than four carbon atoms of which valine is
the first representative. Its composition is shown in the fol-
lowing table:

Valine Leucine Isoleucine

CHEMICAL COMPOSITION OF THE CELL 41

Together with the valine we find in the above table two
other Bausteine, leucine and isoleucine, which differ from each
other by the form of their carbon skeletons.

The multiplicity of these chemical forms is increased by
the fact that the number of COOH and NH, groups attached
to one and the same carbon chain may vary. We find, for ex-
ample, in the adjoining table, two amino-acids, one of them
glutamic acid containing two COOH groups, the other ormthine
containing only one COOH group but two NH, groups. Natur-
ally the characters of these two Bausteine are altogether differ-
ent. The first is an acid, while in the second substance basic
properties predominate.

TABLE V

CH,-NH, COOH

| |
CH: CH,

| |
CH, CH.

| |
CHNH, CHNH,
| |
COOH COOH
Ornithine Glutamic Acid

But I do not wish to weary you with the further enumera-
tion and closer characterization of these substances. I will
only say that in the amino-acids we have a group of which it
may be well said:

‘Alle Gestalten sind ihnlich und keine gleichet der andern
Und so deutet das Chor auf ein geheimes Gesetz.’’

In the living cell these substances are found partly in the
free state, but chiefly in combination. Under normal econdi-
tions they do not accumulate in the free state to any consid-
erable extent, but this does frequently happen under pathologi-
eal conditions. I need only mention the appearance of cys-
tine, glucose, and the higher fatty acids in certain abnormalities
of metabolism. It is also well known that these substances are
often stored up in considerable amount in ripening seeds.

42 HARVEY SOCIETY

Other considerations confirm us in the belief that the Bau-
steine of protoplasm play an independent role in the organism.
A particularly instructive and well-known example is the for-
mation of hippuric acid following the introduction of benzoic
acid into the animal body. This change is brought about so
that the glycocoll or amido-acetic acid is attached to the benzoic
acid administered. Thus we see that the glycocoll not only
appears as a chemical unit when we decompose animal tissue
by artificial means, but also that it can react as a unit in the
processes taking place in the living body.

The same thing is true in the case of some other amino-
acids, such as ornithine and cystine, and in the case of certain
other Bausteine of protoplasm, such as glucose, for example.
All these substances may react, at least to some extent, in the
free state, as does glycocoll. They may attach themselves to
substances which may be introduced into the animal body, and
thus it is certain that they may react as independent groups
in metabolic processes.

As I have previously said, in most cases these Bausteine
are found not as chemical individuals but as parts of a larger
complex. Thus are formed the most various substances which
we know as fats, carbohydrates, phosphatides, and proteins.
I have already spoken of their different types of union. In
some cases we find the Bausteine united to the larger com-
plexes by means of oxygen, in other cases by sulphur or nitro-
gen. In those cases where the union is effected by means of
nitrogen we find that one of the three valences of nitrogen is
united with one of another Bausteine, while the third valence
is attached to hydrogen. The linkage is thus effected by an
NH group or ‘‘ imino-group.’’ When a large number of amino-
acids are joined to each other in this fashion there are formed
large aggregates which are known as albumins or proteins.

The fats present a very simple form of union in which the
triatomie alcohol, glycerin, is united with three fatty acid
molecules. The phosphatides form a more complex group and
apparently contain combinations of most varied kind, of which
some are still unknown to us. In the carbohydrates we also

CHEMICAL COMPOSITION OF THE CELL 43

find the linkage brought about by oxygen. These Bausteine
have a skeleton containing five or six carbon atoms which are
bound together in large or small numbers. The linkage by
sulphur is only met with in exceptional cases as in the pro-
teins together with the imide forms. These imide linkages are
the predominant form present in the proteins. An example is
shown in the following formula representing the combination
of a glycocoll with an alanine molecule:
NH,:CH,:CO NH-CH- COOH
CH,
Glycylalanine

The larger groups formed by the union of many Bausteine
are those which the chemist first encounters in his analyses.
Thus up to the present it has been customary to consider the
proteins, polysaccharides, fats, and phosphatides as the physio-
logical units rather than the protoplasmic Bausteine. When,
therefore, I regard the smaller protoplasmic fragments as the
reacting units, I find myself to a certain extent in opposition
to the usual point of view, and this conception of mine should
not be generally adopted without further consideration.

As a matter of fact, when we consider the physiological réle
of the larger aggregates, such as the proteins, it is necessary
for us to distinguish between those functions which may be
considered as due to the sum of the individual Bausteine
and those which depend on the mode of union of these Bau-
steine. In the latter case it is the particular formation of
the whole molecule which is of importance. This latter
is obviously the case where the form of living parts is dependent
upon the constituents, as, for example, is the case with cellulose,
chitin, and the horny substance of the skin. In other cases it
would appear that the function of certain substances is not
dependent upon their chemical composition, but it is rather
their physical consistence that renders them of value to the
organism. In these cases the proteins function as a whole,
and probably this is also the case with the muscle proteins con-
cerned with the transmission of mechanical and thermal stimuli.

44 HARVEY SOCIETY

This is true, too, of the proteins of other parts concerned with
the reception and distribution of stimuli.

There are many other important functions which are de-
pendent upon the chemical peculiarities of the whole molecule.
As an example I may mention the taking up cf oxygen by the
coloring matter of the red blood-cells. The large protein mole-
cules are so arranged that they easily react to feeble chemical
influences, and this reactivity is undoubtedly related to their
physiological role.

The foregoing examples differ from those cases in which we
find large molecules, especially in the case of the carbohydrates
and proteins, which are to be regarded simply as storage forms
of the smaller active components. The proteins, the polysaccha-
rides, and other similar aggregates act in this manner when
they are employed as foodstuffs. The particular forms of com-
bination which are characteristic of the large molecules are de-
stroyed in the process of digestion. Specific ferments decom-
pose the polysaccharides; others the fats or phosphatides; others
the nucleic acid; and still others resolve the proteins into their
Bausteine. The individuality of the proteins is completely lost
save for the quantitative relations of the Bausteme, which un-
dergo absorption and are utilized for the various purposes of
the body.

We may regard the storage of carbohydrates, fats, and pro-
teins in the same way. They form a reserve of nutrient ma-
terial which is attacked and utilized according to the neces-
sities of the organism. At certain times ferments come into
play in the tissues which decompose the larger aggregates into
their Bausteine, which then play a part in metabolism as in-
dividual units. Glycogen, for example, which is readily stored
up as the result of a generous diet, at other times is resolved
into glucose molecules, that is to say into its Bausteine. Pro-
teins in the same way are decomposed by active tissue ferments
into their Bausteine, which are then utilized in the course of
metabolism.

The importance of this resolution into Bausteine ean only
be fully appreciated when one considers that out of these same

CHEMICAL COMPOSITION OF THE CELL = § 45

Bausteine entirely new structures may be built up in other
parts of the organism. For example, if an animal is fed with
fat, the fat is resolved into its Bausteine in the intestinal
eanal, but it may be resynthesized, on absorption. Fat in the
process of transportation through the intestinal wall may be
compared to a portable house which may be taken apart in one
place to be reconstructed in another.

When the proteins undergo a similar process, involving their
decomposition and subsequent re-formation, a change in the
character of the synthesized protein may be effected. Thus the
body is able to build its own protein substances from foreign
proteins. This reconstruction of the proteins is so interesting
and so physiologically important that I should like to make
further reference to it. I should like to compare this rear-
rangement which the proteins undergo in the animal or vege-
table organism to the making up of a railroad train. In their
passage through the body parts of the whole may be left be-
hind, and here and there new parts added on. In order to
understand fully the change we must remember that the pro-
teins are composed of Bausteine united in very different ways.
Some of them contain Bausteine of many kinds. The multi-
plicity of the proteins is determined by many causes, first
through the differences in the nature of the constituent Bau-
steine; and secondly, through differences in the arrangement
of them. The number of Bausteine which may take part in
the formation of the proteins is about as large as the number
of letters in the alphabet. When we consider that through the
combination of letters an infinitely large number of thoughts
may be expressed, we can understand how vast a number of
the properties of the organism may be recorded in the small
space which is occupied by the protein molecules. Tt enables us
to understand how it is possible for the proteins of the sex-cells
to contain, to a certain extent, a complete description of the
species and even of the individual. We may also comprehend
how great and important the task is to determine the structure
of the proteins, and why the biochemist has devoted himself
with so much industry to their analysis.

46 HARVEY SOCIETY

The first step in these lengthy investigations consists in the
determination of the quantitative relations which the Bau-
steine in the protein molecules bear to each other—how much
of one and how much of another Baustein is present in the
large protein molecule. Methods have been worked out for
the determination of some of the amino-acids, to estimate the
quantity of leucine, alanine, histidine, and lysine in different
proteins. The results of these analyses are presented in such
a way that one may see the percentage quantity of any par-
ticular Baustein in the different proteins.

This represents merely the beginning of our investigations,
and may be compared to a man attempting to read a book in
some foreign language who at first can only determine the
numerical relation between the different letters of the alphabet
in each section of the book.

I should like to illustrate this by an example. It has been
possible to remove from proteins some large fragments and
successfully investigate their constitution. In this way the
relative position of individual Bausteine in the protein mole-
cule can be determined, and this again may be compared to
the deciphering of separate syllables. Furthermore, it has
been possible to reconstruct artificially such compounds and
compare the synthetic with the natural products. In this way
a knowledge of the chemical make-up of the protein substances
may be slowly gained. On the other hand it is possible to find
in nature substances which may be regarded as simplified pro-
teins, and the constitution of these is more readily investigated
than the complex typical proteins. The following is an example
of their formation:

Observations upon the life-history of the Rhine salmon
show that this fish at certain times lives in the sea; at others
in fresh water. During the period of life in the sea, he eats
freely and devotes himself to the acquisition of a sufficient
quantity of protein in his body to serve him for a long time
(on an average about ten months) in the river, where the for-
mation and storing of the sexual products take place. While
in fresh water he takes no food of any kind, and the proteins

CHEMICAL COMPOSITION OF THE CELL 47

of the body muscles are used up to a large extent, while the
male or female sexual products are being formed. During
this time the animal may be compared to a patient in whose
body is formed a tumor, the tissue material of which is slowly
gathered from the whole body. By the beginning of November
the development of the sexual products has reached its high
point. If at this time we kill the male animal and compare
the protein of the newly-formed male sexual products with the
protein which in the course of the development of the testicles
has disappeared from the muscles, we find a peculiar relation-
ship. Of twenty Bausteine present in the used- -up protein, only
four or five kinds are present in the newly-formed proteins.
We must conceive of the process as taking place first of all by
the resolution of the protein into its individual Bausteine.
Some of these Bausteine are completely decomposed during the
starvation period of the animal and others of special kinds re-
main protected from decomposition and are united to form a
new protein substance—the so-called salmine.

Similar transformations of proteins into other protein sub-
stances possessing totally different characters from the original
one take place when foreign proteins are used for food. In
the seeds of many plants proteins are contained which differ
in their composition from the proteins of the animal organism.
This difference is due to the absence of certain Bausteine which
are present in the animal protein. Moreover, they possess
different solubility relationships. Zein, the protein of maize, is
an example of this kind. If a young goose is fed for several
months with maize so that its body substance is materially
increased, we find on investigation of its or gans that the Bau-
steine of the maize have been used for the synthesis of a new
animal protein. This process of reconstruction is seen to oc-
cur when a mammal such as a dog or mouse is given only
Bausteine instead of intact protein substances. In this case it
is possible to demonstrate the formation of the proteins charac-
teristic of the animal’s own body.

Similar phenomena are observed in the ease of other chemi-
eal constituents of the tissues, such as carbohydrates and fats.

48 HARVEY SOCIETY

It has long been known that glucose when introduced into the
body leads to glycogen formation, while fatty acids unite with
glycerine and are built up into fats.

Thus far we have been considering the Bausteine, the na-
ture of their union, and their formation from large groups,
without considering the questions of their origin and of their
significance in metabolism. I propose to touch on these prob-
lems but lightly.

When in the seventies the early observations upon the
structure of the cell nucleus were made, it was correctly be-
lieved that a most important step forward had been taken.
The histological structure of the nucleus and its changes in
form were rightly considered characteristic of the individuality
of the organs. These nuclei are found throughout the whole
world of living organisms, and form an ‘‘ Hinheit in der
Vielheit’’ of living phenomena. Karyokinesis is brought into
relation with the function of cell division and growth of living
substance. It is obvious that it would be of even greater im-
portance if we could correlate the changes in chemical struc-
ture with these histological peculiarities. It would give us a
deeper insight into the significance of these parts of the liy-
ing substance if we could determine a particular atomic group-
ing which would be typical for the cell nucleus or for its
functions.

It seems to me that such a determination may be derived
from investigations upon the chemistry of these elementary
parts. If we compare the atomic groupings of the cytoplasm
with those of the karyoplasm, we find that long carbon chains
either free from or poor in nitrogen predominate in the first.
This is also the case with the fatty acids and the carbohydrates.
Furthermore, the proteins of the cytoplasm are to a large ex-
tent made up of the union of monamino-acids which contain
only one nitrogen atom in a large series of carbon atoms.
Such is the case, for example, with leucine, valine, tyrosine, or
alanine and most of its derivatives.

If we now compare the atomic groupings which are char-
acteristic of the cell nucleus, and which have already been re-

CHEMICAL COMPOSITION OF THE CELL 49

ferred to as constituents of the nucleic acids (Table II) we
see, in the first place, an abundance of nitrogen, and secondly
a peculiar grouping of this element between the carbon atoms.
This is particularly characteristic in the cyclic complexes
which are known as pyrimidine and purine derivatives. In
many of these compounds, such as adenine for example, we find
a nitrogen atom attached to every carbon atom and the arrange-
ment is such that C and N alternate with each other in the
formula.

Similar atomic groupings are found in certain special Bau-
steine which make up the protein molecule. It is found that
those proteins which occur in the cell nucleus are very rich in
these groups. This is particularly true of the so-called amidine
group which we find in arginine and which exhibits the accu-
mulation of nitrogen shown in the following formula:

NH, —C = NH—NH-C:.----:::--

In certain nuclear substances a particularly large amount
of histidine is found. This substance belongs to the iminazol
group and has the cyclie structure shown in Table III.

These observations compel us to assume that these peculiar
linkages of the carbon and nitrogen atoms stand in close re-
lation to the functions of the cell nucleus and especially that
concerned with building up new material.

When the proteins of the yolk of insect or hen’s egg are
converted into young, growing cells, whose function it is to
furnish rapidly new tissue, a rearrangement of the atoms takes
place in such a way that these peculiar carbon and nitrogen
linkages are stored up in the cell nuclei.

The foregoing observations do not exclude the possibility
of the same atomic group appearing in other places in the
tissues and subserving other physiological functions. Thus
for example we find the purine ring in guanine as a constituent
of the skin of many organisms in the form of erystals, which
apparently influence the color through their optical properties.
Or we may find the purine ring among the end products of ani-
mal metabolism, since the cyclic grouping is relatively resistant.

50 HARVEY SOCIETY

Let us now glance once more at the peculiar chemical re-
lations of the cell nucleus. Here we find substances of acid
property, the nucleic acids which exist in different forms.
These substances have acid properties, and long since I have
put forward the view that they are to be considered as poly-
metaphosphorie acids containing, therefore, a chain of phos-
phorus and oxygen atoms to which the previously mentioned
pyrimidine and purine derivatives as well as carbohydrates are
attached.

In the cell nucleus these substances are united only with
proteins, and these combinations may be of various kinds. In
some cases the combination is quite stable, so that it is impos-
sible to resolve it without destruction of the whole chemical
structure. In other cases the nucleic acid is united with the
protein in a loose salt-like combination which is readily de-
composed under the influence of a stronger acid. This is
observed in those cases in which the proteins of the cell nucleus
are made up of basic molecules such as the histones. It may
be said, therefore, that there are two types of nuclear sub-
stances occurring in the different cell nuclei. I may refer to
these as the dissociated and non-dissociated forms. It would
seem likely that microscopical differences between the two
forms of cell nuclei may be found.

The question presents itself as to whether it is possible to
correlate physiological relationships with these two forms of
cell nuclei. Up to the present, so far as I know, this has
not been possible. In the same organ of one species we find
the dissociated, of another species, the non-dissociated forms.
For example the nuclei in the heads of the spermatozoa of
warm-blooded animals appear to be non-dissociated, so far as
my investigations go, while on the other hand they are dis-
sociated in the ease of fishes. In the internal organs of higher
animals both forms are encountered side by side.

These considerations show us how the methods of biochemi-
cal analysis may be utilized for the attainment of a knowledge
of living processes.

CHEMICAL COMPOSITION OF THE CELL 51

While the experimental physiologist approaches the living
organs with a definite supposition of hypothesis and plans his
experiments with reference to this preconceived idea, the histo-
chemist carries on his investigation unhampered by such defi-
nite preconceptions, and usually cannot foresee the nature of
his results. The descriptive and the experimental method
must go hand in hand in the investigation of living function.
The ideas derived from the one are carried further by the
other.

When nowadays we regard it as necessary to separate the
experimental and descriptive sciences, to separate anatomy
and physiology, and the chemical and physical methods of
investigation, it involves the breaking of 2 natural continuity.
Such separation is only necessary because of the limitations
of individual human endeavor, for it is impossible for a single
person to master all the methods and to familiarize himself
with so vast a wealth of material.

NARCOSIS*

PROFESSCR MAX VERWORN
University of Bonn

WO main reasons induced me to select the subject of nar-
cosis for my lecture before your society. On the one
hand, I am following herein the suggestion of your honored
President; on the other hand, the problem of narcosis has a
personal attraction for me, since with my colleagues at Gottin-
gen, as well as in Bonn, I have devoted a great deal of attention
to its investigation. Furthermore, I believe that this theme, the
subject of narcosis, possesses an especial interest for medical
men, not only from the theoretical but also from the practical
side. From the theoretical side, because the processes of nar-
cosis introduce us into the most profound secrets of the
mechanism of living matter; from the practical side, because
it is incumbent upon the physician to know the actual nature
of the condition which he so often induces in man. Practical
and theoretical interests have here, once more, the same object.
Such union of practical and theoretical interests makes our
medical work so fruitful and lends it a special charm among
the biological sciences. This is especially manifest in the
study of the peculiar phenomena of narcosis, and is also the
reason why the subject of narcosis has been so extensively in-
vestigated, especially in the latter decades.

The knowledge of the use of narcotic substances, especially
those from the vegetable kingdom, is ancient. It extends back
to prehistoric times, as we may deduce by analogy with primi-
tive races living to-day. Man has been, from the first, a stu-
dent of nature. He was forced to adapt himself, at every step, -
to his environment. This he could do only by very close ob-
servation of nature, for there was danger lurking for him

“* Delivered October 28, 1911.
52

NARCOSIS 53

wherever, in his wanderings, he was confronted with new con-
ditions. ‘Thus, in his quest for food he had to learn to recog-
nize the peculiar poisonous effects of plants. All primitive
races are familiar with them and employ them for various
purposes. The use of nareotizing substances, especially for
purposes of enchantment, was well known in the Homeric age.
Circe mixed narcotic juices with the food of the companions
of Odysseus, making them forget their homes; and Hermes
knew already an antidote, which he gave to Odysseus as
a protection: pa@iv o8 piv xzaklovot Gent. In Homer we also
find, for the first time, although not in connection with poison-
ous action, the word from which the modern term ‘‘ narcosis ”’
ig derived. The verb vapxdw, “‘T am paralyzed,’’ appears
in Homer as dza& elpnpévov when he deseribes how Hee-
tor struck Teukros on the shoulder with a sharp stone, so
that his hand, paralyzed, let fall the bow (Iliad VIII, 328).
This venerable word serves us to-day to distinguish a special
group of paralyses, or depressions, which are induced by
chemical substances.

The scientific study of narcosis begins, however, only with
the time when narcotics came into general use in medical prac-
tice for the relief of pain, especially since, in Boston, in 1846,
the chemist Jackson and the dentist Morton introduced ether
into surgical practice. Soon after this momentous event ex-
periments began for the purpose of explaining the striking
action of anesthetics. Among the numerous explanatory ef-
forts, however, there are only two series of attempts which de-
serve scientific consideration.

In one series attempts have been made to establish a relation
between the depressing action of narcotics and their solubility
in certain constituents of the organism. As early as 1847,
Bibra and Harless used the fact that cerebral fats are readily
soluble in such narcotics as ether and chloroform, as a basis
for a hypothesis of the mode of action of narcotics. They
assumed that the narcotics act as anesthetics by extracting the
brain fats. Hermann indicated later a similar conception, and

54 HARVEY SOCIETY

recently Reicher has shown that in deep and long-continued
narcosis the fat content of the blood rises indeed quite mark-
edly. While already in these assumptions the relations of
solubility between fats and narcotics stand in the foreground,
Richet has later on called attention to a second relation in
regard to solubility. He noticed that many narcotics were
distinguished by a very low degree of solubility in water, and
believed that, on the basis of his observations, he could make
the general statement that a substance acts the more strongly
as a narcotic, the less it is soluble in water. The relations be-
tween the solubility of narcotics in fats and water and their
depressing action, which in the before-mentioned observations
and hypotheses were expressed so incompletely and obscurely,
were first made clear and formulated according to definite
laws by Overton and by Meyer, independently of one another.
Hans Meyer and Overton were able to show that the intensity
of the narcotic action of any substance is dependent on the
proportion in which it is distributed between water and fat
when it is shaken with a mixture of fat and water. The co-
efficient of distribution, that is, the proportion of solubility of
the substance between water and fat, is the greater, the
stronger its narcotic action. That is to say, a substance acts
the more strongly as a narcotic, the more soluble it is in fats
and lipoids and the less soluble it is in water. Meyer and
Overton have confirmed this law in the ease of a very large
number of narcotics. This interesting fact contains apparently
a very important requirement for the production of narcotics,
although it does not present a ‘‘theory of narcotics,’’ as has
often been incorrectly stated. It shows us one factor that
must be realized if the narcotic is to reach its field of action,
but it tells us nothing concerning the mechanism of the nar-
cotizing action itself.

The second series of explanatory attempts ascribes the de-
pressing action in narcosis to a change in the state of aggre-
gation of certain components of the protoplasm under the in-
fluence of the narcotic. Claude Bernard, who noticed the

NARCOSIS ; 55

rigidity of muscles which is produced by the influence of
chloroform vapor or heat, was the first one to express the view
that narcosis consists in a ‘‘ semicoagulation ’’ of the proto-
plasm. Binz came to the same conclusion from a microscopic
study of ganglion cells and unicellular organisms. He found
that the protoplasm of the cells became opaque, granular, and
dark under the influence of the narcotic, as is the case in
coagulation, and he sees therefore, in narcosis, a depression by
coagulation. As a matter of fact, it is easy to observe such
changes in unicellular organisms under the influence of large
doses of narcotics, but recovery from such a state is no longer
possible. In recent times, Hober has expressed similar
opinions. Hoéber makes the hypothesis that the process of
excitation is associated with a loosening of the protoplasmic
colloids, which consist of lipoids and proteids. In connection
with this assumption, Hober offers the further hypothesis that
nareoties inhibit this loosening of the colloids, especially in
the superficial protoplasmic layers of the cell, so that in con-
sequence the irritability is reduced or abolished.

Thus, we see that widely different hypotheses concerning the
nature of narcosis have been expressed, without any of them
having as yet achieved general acceptance.

Before we attempt to form a conception of the mechanism
of narcosis, it appears to me indispensable that we clearly un-
derstand what should be required of any theory of narcosis.
Narcosis is a state of living matter, in which, under the in-
fluence of certain chemical substances, the physiological proc-
esses of the cell are altered in a special way. A scientific study
of this state can consist only in seeking to determine, as far
as possible, the nature of these changes. The more deeply we
analyze them, the clearer becomes the theory of narcosis. In
order, however, to comprehend the changes in the physiological
processes in living matter, it is requisite that we should first
know the normal physiological processes themselves, in all
their details. In spite of many important and fundamental
researches, we are to-day still far from such knowledge. From

56 HARVEY SOCIETY

this it is evident that we cannot yet speak of a ‘‘ final ’’ theory
of narcosis. But where in our knowledge do we arrive at final
results? Wherever we may look, whatever we may achieve,
we are always and again confronted with new problems. Is
there, anyway, a finality anywhere? Whoever, impatiently
rushing forward, looks for a final word in knowledge will,
like Goethe’s Faust, only experience grievous disappointment :

“Entbehren sollst Du, sollst entbehren!
Das ist der ewige Gesang,
Der jedem an die Ohren klingt,
Den unser ganzes Leben lang
Uns heiser jede Stunde singt.”

On the other hand, whoever is conscious that all things
stand in endless coherence will desist from seeking an imagi-
nary goal, and instead will enjoy the inexpressible charm which
lies in the unlimited possibilities of finding again and again
new links of this coherence. The possibilities of knowledge
are endless, because the world is endless. This is true in large
as well as in small things, and is true also of our problem.
To the extent to which we succeed in discovering new facts
which characterize the state of narcosis, to that extent the
theory of narcosis develops of itself.

Well, then, what do we know of the changes which living
matter undergoes during narcosis? Narecosis is a state of
depression. Let us understand what this means. All states
of depression in living systems are characterized by the fact
that all or single partial processes of the normal metabolism
undergo a retardation of their course, which may amount to
complete standstill. This shows itself in the following symp-
tom complex. The specifie manifestations of life of that
system are depressed or extinguished. The irritability to ex-
ternal stimuli is lowered, so that stimuli which are effective
in the normal state show no apparent result. At the same
time the power of conductivity, that is, the transmission of the
excitation from the point of stimulation to some distant place,
is correspondingly restricted, for irritability and conductivity

NARCOSIS 57

run always and everywhere along parallel lines. This symp-
tom complex occurs in the most diverse living systems and un-
der the influence of manifold agencies. We see it as a result
of low temperatures in ‘‘frigor depression,’’ or as a result of
high temperatures in ‘‘ heat depression ’’; we meet it after ex-
treme functional activity, as fatigue; after withdrawal of
oxygen, as suffocation; under the influence of chemical sub-
stances, as toxic depression; after too low osmotic pressures
of the surrounding medium, as ‘‘ water rigor ’’; from stoppage
of the blood supply to the tissue cells, as asphyxial depression ;
and under many other conditions.

The question now arises, whether the mechanism of the de-
pressing process is the same under all these widely diverse
circumstances. In its generality, we can at once answer this
question in the negative. The mechanism of depression in
water rigor and in acid intoxication, for instance, is entirely
different. Nevertheless, comparative studies of the mechanism
of depression under the influence of different factors have
shown me that a particular tendency exists toward one etiologic
type of depression. In the complex realm of metabolism in
all aérobie forms of cell, one part of the many anabolic and
catabolic processes is especially sensitive to external influences,
and that is the oxygen metabolism. Here is, in a certain sense,
the locus minoris resistenti@ of the living matter of all aérobic
organisms. In fatigue, it is the relative deficiency of oxygen
which produces the depression. The increased demand for
oxygen, brought about by the increased functional activity,
ean no longer be satisfied by the amount of oxygen present.
The same is true of heat depression. The supply of oxygen
cannot keep pace with the accelerated catabolism of the living
tissue, induced by the temperature. In the asphyxial depres-
sion of the tissue cells which occurs as a result of any stoppage
of the blood supply, it is not the withdrawal of the organic
nutritive materials in the blood, but only the lack of oxygen,
which produces the depression. In prussic-acid poisoning,
again, it is the suppression of the oxygen metabolism in the

58 HARVEY SOCIETY

tissue cells which produces death. Thus we see that oxy-
genation is the factor, in the metabolism of aérobic cells, which
most easily fails under diverse external influences and so
forms the starting-point for the development of depression.
The most simple paradigm of this entire group of depres-
sions is therefore suffocation of living cells or tissues in indif-
ferent media free of oxygen. Fortunately we know to a
certain extent the working of the mechanism of suffocation.
In normal metabolism during rest the supply of oxygen is
always sufficient for the needs of the cells. Molecular oxygen
is absorbed by them from the surrounding medium, A certain
reserve supply of molecular oxygen, although comparatively
small, is always present in the cells themselves, at least in cold-
blooded animals not kept at too high a temperature. Many
facts force us to this opinion, especially the continuance of
normal production of energy and of irritability for a longer
or shorter time, under complete exclusion of oxygen supply.
The oxygen taken up from the medium is activated by special
oxygen carriers and distributed to the oxidizable substances.
We know of the existence of such oxygen carriers in the most
diverse animal and vegetable cells, and we are accustomed to
group them together under the collective name of ‘‘ oxydases,’’
although their chemical constitution is still completely un-
known. The oxygen carriers bring activated oxygen, in the
manner of inorganic catalysators, to the oxidizable substances,
which by the oxidation are split into carbon dioxide and water.
One point here remains still undecided, and that is, whether
the oxidation attacks the organic fuel directly, such as, for
instance, the carbohydrates, which have been synthetically
built up by anabolic processes, or whether only the fragments
are oxidized to carbon dioxide and water, while the splitting
itself is accomplished by enzymatic processes. It is possible
that in different forms of living substances the catabolism
takes a different course. At any rate, the principal source of
energy in all aérobie organisms is to be found in the oxidative
splitting-up processes, and not in the non-oxidative part of the

NARCOSIS 59

catabolism. These oxidative splitting-up processes represent
the principal source of energy production. That is an im-
portant fact. It has a special bearing upon the degree of
irritability of living matter, for irritability is measured by
the amount of energy production which results from a
stimulus.

What changes does this phase of metabolism undergo, when
the external supply of oxygen is withdrawn from a living.
system? No more molecular oxygen enters the living matter
from the outside. The molecular oxygen, which at the moment
of exclusion of oxygen is still present in the living tissue,
will, according to its amount, be used up sooner or later. In
the same proportion the extent of the oxidative breakdown
will decrease. The catabolism will occur more and more in
a non-oxidative manner. As soon as all the oxygen is used
up, the destructive process will be entirely non-oxidative. This
gradual transition from oxidative to exclusively non-oxidative
decomposition corresponds in a characteristic way to the
development of the depression. The intensity of the sponta-
neous vital activities diminishes gradually after the interrup-
tion of the external supply of oxygen. Very gradually the irri-
tability for external stimuli decreases. Very gradually also
the extension of the excitation from the point of stimulation
to adjacent parts becomes restricted. Finally no sponta-
neous manifestations of life are visible; finally no visible effect
is to be obtained from the strongest external stimuli. These
are the general consequences which result from an interruption
of the oxygen supply and which we observe everywhere in
whatever way and at whatever point the oxygen metabolism is
disturbed.

I have dwelt in some detail on the relations of the metab-
olism of oxygen and its disturbances, because our investiga-
tions carried out in the laboratories at Go6ttingen and Bonn
have shown that in narcosis, also, there is a similar interference
with the oxidation process. The fact that the oxygen metab-
olism suffers readily under diverse external influences sug-

60 HARVEY SOCIETY

gested the question whether also, under the influence of nar-
cotics, disturbances of the oxidative processes take place. I
had previously studied, by means of an artificial circulation,
the réle of oxygen metabolism in fatigue of the spinal cord
of the frog, made especially sensitive by mild strychnine
poisoning. It seemed to me, from my experience, that this
would be a favorable object for the experimental determination
of the question whether the oxidative processes are interfered
with during narcosis. This question could be particularly well
studied on the fatigued spinal cord, because it was found that
the fatigue can be completely removed again only by the
supply of oxygen. If the spinal cord is fatigued and oxygen
is not supplied, as can easily be arranged with an artificial cir-
culation, and if now the completely fatigued and oxygen-greedy
spinal cord is narcotized, it can be determined whether,
with a free supply of oxygen, the spinal cord can take it up,
and thus recover during narcosis. If the fatigued cord is
irrigated during narcosis with arterial ox blood or with an
oxygen containing saline solution, and later, while the narcosis
still continues, the blood is removed again by oxygen-free salt
solution, and if then the narcosis is stopped, it must become
manifest whether the centres of the cord have taken up the
abundantly supplied oxygen during narcosis, and recovered.
Winterstein has performed this experiment at Gdéttingen,
using various narcotics, such as ether, alcohol, chloroform,
and carbon dioxide. All the experiments agreed in showing
that not the least trace of recuperation occurred; while, after
the end of the experiment, the cord was completely restored
in a few minutes by perfusion with oxygenated ox blood with-
out narcosis. Herewith the first proof was given that, during
narcosis, living tissues are unable to utilize the oxygen offered
to them.

Nerves offered a second favorable object for testing our
question. We had succeeded, after many vain attempts, in
perfecting a method by which it was possible to show that
nerves died of suffocation when eut off from all possible supply

NARCOSIS 61

of oxygen. This fact, established by H. von Baeyer, placed
us in a position to make on the nerve, which proved to be an
exceedingly favorable object, experiments on the question of
oxygen metabolism during narcosis analogous to those made
on the cord. The sciatic nerve of the frog was asphyxiated,
and thus made oxygen greedy. When its conductivity was
lost and its irritability reduced to a very low level, it was
nareotized with ether. Then, during narcosis, oxygen was
supplied to it for a long time. After the oxygen had been
finally removed by pure nitrogen, the narcosis was stopped.
In these experiments, which were first made by myself, after-
wards by Frohlich, and later on by Heaton, there was never
any trace of recovery. When the nitrogen was replaced by air,
the nerve recovered in one minute and showed normal irrita-
bility and restoration of conductivity.

Finally, in a series of experiments which have not yet been
published, Ischikawa proved that amcebe, also, which had
been asphyxiated in a gas chamber in pure nitrogen and had
become motionless, did not take up oxygen which was supplied
to them during narcosis, while after stopping the narcosis
and replacing nitrogen by air they rapidly resumed their
amceboid motion.

These experiments show unequivocally that living tissues,
even when their demand for oxygen has been raised to an
extreme degree by fatigue or asphyxia, cannot, during narcosis,
make use of oxygen, even when offered to them abundantly.

This conclusion caused us to advance one step further. If
living tissue, during narcosis, cannot use the oxygen which is
supplied to it, this inability might be produced in several
ways. Either narcosis depresses the entire phase of catabolism,
with all its partial processes, perhaps by paralyzing the
first step, or it hinders especially only the oxidation processes.
In the former case, we should expect that a narcosis of a cer-
tain depth, in which the destructive processes were completely
abrogated, could continue for an indefinite time. In the
second alternative, that is, if only the oxidation is prevented,

62 HARVEY SOCIETY

destruction must proceed in non-oxidative form, just as in the
absence of external oxygen supply, and the living tissue under
narcosis must eventually die of asphyxia, even though suffi-
cient oxygen is constantly at its disposal. We can decide
between these two possibilities. On the one hand, experience
shows that no narcosis, whatever its depth, can continue indefi-
nitely without the tissue losing its viability. On the other
hand, we can demonstrate experimentally that during narcosis
catabolism proceeds in non-oxidative manner and that as-
phyxia gradually supervenes. Here again the nerve proved to
be a favorable object for experiment. Heaton has used the two
sciatic nerves of the same frog for the following parallel
experiment: One nerve was drawn through a gas chamber
which contained pure nitrogen; the other was narcotized in
a similar gas chamber filled with air. The experiments began
simultaneously in the two nerves. In the asphyxiated nerve
the irritability sank very gradually lower and lower. When
it had fallen to a certain level, the conductivity for an excita-
tion coming from the part of the nerve outside of the gas
chamber vanished also. The time at which this degree of
depression is reached depends on the length of the asphyxiated
portion of the nerve, on the condition of the frog, and on the
temperature. At room temperature it requires, on the average,
from two to three hours. At the time that the conductivity
of the asphyxiated nerve was abolished, the air surrounding
the narcotized nerve was replaced by pure nitrogen, and the
narcosis interrupted, so that the nerve, after the narcosis was
stopped, had no more oxygen at its disposal. If the whole
destructive. phase of metabolism had been brought to a stop,
the nerve should, after stopping the narcosis, be in about the
same condition as before it. This was, however, not the
ease. All the experiments, rather, agreed that during narcosis
this nerve was also asphyxiated like the nerve in pure nitro-
gen, in spite of the fact that the former always had air
at its disposal. Its irritability had been greatly reduced and
its conductivity was abolished. That it was actually asphyxi-

NARCOSIS 63

ated was shown by the control experiment, in which both nerves
recovered completely as soon as air was conducted over them.
The irritability increased rapidly as the conductivity returned.

Ischikawa has recently performed similar experiments on
ameebe. Ameebe gradually lose, in nitrogen, their amcboid
motions. They regain them only when oxygen is supplied.
If amcebe are narcotized with ether, they are also asphyxiated;
for after the narcosis, in the absence of oxygen, they do not
regain their ameboid motions. These only return after oxy-
gen is supplied.

It is thus evident that living tissue is asphyxiated during
narcosis; that is, that the destructive phase of metabolism
proceeds in a non-oxidative manner.

We can add yet another fact. Even during narcosis the
destructive processes can be increased, that is, accelerated, by
exciting stimuli. Teaton has narcotized the two sciatic nerves
of a frog in a double chamber under absolutely identical con-
ditions. While one of them remained at rest, the other was
continually stimulated by a faradic current applied to the
end beyond the chamber. After discontinuing the narcosis
in pure nitrogen it was always found that the irritability of
the stimulated nerve had fallen to a lower level than that of
the other. Placed in air, both recovered to an equal degree.
The results of this experiment entirely agree with the phenom-
ena of fatigue, which were found by Thoérner in his researches
on the fatigue of nerves in nitrogen. On the basis of all these
experiments, we may make the following statement: Living
tissue becomes asphyxiated during narcosis. The catabolic
phase of metabolism continues in the form of a non-oxidative
destruction, just as in asphyxia, and can also, as in asphyzia,
be accelerated by exciting stimuli. Recovery from this
asphyxia is, as in every asphyxia, only to be attained by sup-
plying oxygen.

Under these circumstances the idea naturally presents itself,
that the entire symptom complex of narcosis is only a mani-
festation of asphyxia, which the narcotic induces by inhibi-

64 HARVEY SOCIETY

tion of the oxidative processes. Before we accept this idea,
however, we must assure ourselves that there is no fact which
stands in the way of its acceptance. It goes without saying,
that if asphyxia occurs in narcosis, the general picture of
asphyxia must be present. This is actually the case. The
cessation of spontaneous evidences of life, the reduction of
irritability, the decreased power of conductivity—all the typi-
cal symptoms are identical in narcosis and in asphyxia in an
oxygen-free medium. In only one point is there a noteworthy
difference. That is in the time relations of the depression
symptoms. In narcosis of nerves, for instance, irritability
sinks in a few minutes to a point which in pure nitrogen is
only reached in two or three hours. The question therefore
arises, whether we have not here a fact which must inevitably
eliminate the idea that narcosis is nothing more than asphyxia.
A more careful consideration shows, however, that this is not
the case. The experiments which have already been described
contain the explanation of this difference in the rapidity of
onset of the depression.

The fact that living cells, during narcosis, can make no use
of molecular oxygen, even when it is freely offered to them,
shows that the narcotic renders the living tissue incapable of
undergoing oxidations. It cannot, therefore, utilize for its
oxidation processes the oxygen present in itself. The con-
ditions during asphyxia in an oxygen-free medium are, how-
ever, quite different, as for instance in asphyxia of nerves in
nitrogen. Here the power to carry on oxidations is not inter-
fered with in the least. As long as any trace of molecular
oxygen is present, it can be used for oxidation. Now it is of
course impossible that, at the moment that the air in a gas
chamber is replaced by nitrogen, every trace of oxygen should
disappear from the nerve in the chamber. The nerve, there-
fore, with its small oxygen requirement, can, even in pure
nitrogen, carry on its oxidation processes in a more or less
decreasing degree, according to the temperature and to the
amount of oxygen contained in the nerve itself. Accordingly,

NARCOSIS 65

the irritability decreases only gradually, and in proportion
to the extent of the decrease of the oxidative processes. In
the depression of nerves in an oxygen-free medium we deal
with a slow, while in narcosis we deal with an acute, asphyxia.
That is the factor which produces the difference in time. We
have also, therefore, the power of eliminating this difference
completely. We may do this, in one way, by those measures
which hasten asphyxia in an oxygen-free medium. Such a
measure is the increase of the demand for oxygen by raising
the temperature. In this case heat depression occurs. Of
heat depression we know that it is an asphyxia which results
from a relative lack of oxygen, because the supply of oxygen
cannot keep pace with the markedly increased demands of the
living tissue, just as in fatigue. As H. von Baeyer has shown,
complete loss of irritability in nerves may be attained by keep-
ing them for 20 minutes in a gas chamber at a temperature
of 42° to 47° C. The lost irritability cannot be restored by
reduction of temperature alone; while, after supplying the
nerve with fresh air, recovery results in a few minutes. At
higher temperatures asphyxia occurs still more rapidly. In
the ganglion cells of the cerebral cortex of mammals, asphyxia
results in a few seconds when the air supply is cut off. On
the other hand, the narcosis of the nerves can be greatly
delayed if the narcotic is administered only in small amounts.
In short, the more rapid or slow onset of depression ts solely
dependent on the rapidity with which the oxidation processes
are abolished. In narcosis this occurs very rapidly, because
the narcotic renders the cells incapable of carrying on oxida-
tions; in asphyxia in oxygen-free media, it occurs only very
slowly, because the living tissue retains its power to carry
on oxidation and continues to do so until the last trace of oxy-
gen present in the tissues is used up. The difference in the
time of development of the depression in the two cases is solely
dependent on the different way in which the oxidation proc-
esses are brought to a standstill. The symptom complex of
5

66 HARVEY SOCIETY

narcosis, therefore, not only is comprehensible, but on the basis
of the ascertained facts it is inevitable.

It seems to me that, after these considerations, it is no
longer possible to doubt, not only that narcosis is accompanied
by asphyxia, but that the acute asphyxia is the deciding factor
which produces the depression. This does not exclude the
possibility that the narcotic may also produce other changes
in the living matter, for instance changes in the state of ag-
gregation of certain substances. Whatever other changes may
occur, the factor which produces the characteristic symptom
complex of narcosis 1s under all circumstances the suppression
of the power to carry on oxidations.

The conclusions which may be drawn directly from the
facts bring us as far as this; but the problems are by no means
finished. At this juncture the new question arises: In what
way does the narcotic, by entering the cell, inhibit the power
of the latter to carry on oxidations? Here the facts leave us
still in the dark. If we wish to answer this question, it can
only be done in the form of a hypothesis. I wish to empha-
size this point particularly. But ‘‘ no true scientist fails to
realize that the essential factor of progress les in a hypoth-
esis which agrees with the facts.’’ These words of one of
the greatest physiologists, who was also my predecessor in
Bonn, shall serve as my excuse if I attempt now, with the
assistance of a working hypothesis, to go a step further in the
direction indicated.

When we recall the fate of molecular oxygen in the normal
metabolism of the cells, from the moment at which it enters
the living substance to the moment at which it decomposes
the oxidizable materials into carbon dioxide and water, we find
that the narcotic, which overflows the cell, could establish
its inhibitory action upon the oxidation at various stages of
this process.

In the first place we might conceive that the narcotic, when
it has penetrated into the living substance, prevents in some
way the entrance of molecular oxygen from the surrounding

NARCOSIS 67

medium into the cell. This assumption, however, may be dis-
missed at once. If the depression of narcosis were produced
by the fact that oxygen could not penetrate into the cells,
then we could expect a course of depression with exactly the
same time relations as in complete withdrawal of external
oxygen ; the cell would be in exactly the same position as it is,
for instance, in pure nitrogen. The difference in the time
relations between the two cases, for instance in the nerves,
shows us, however, that this is not the case.

Next we must consider the possibility that narcotics ap-
propriate the oxygen which enters the cells, and use it for
their own oxidation. The narcotics are, it is true, generally
looked upon as chemically indifferent substances, but Biirker
has recently published experiments which show that, under
certain conditions, narcotics may be oxidized, at least by
nascent oxygen. Biirker performed the following interesting
experiment: He placed two identical voltameters in the same
electric circuit. One of them was filled with acidulated
water; the other had in addition a small percentage of ether.
Then he decomposed the fiuids electrolytically by means of
a galvanic current. In the voltameter which contained no
ether, the gas collected at the two poles in the usual relation,
the volume of hydrogen at the cathode being to the volume
of oxygen at the anode as 2 to 1. The relationship was, how-
ever, entirely different in the voltameter which contained
ether. Here only a very small amount of oxygen collected at
the anode; while the analysis of the gas from the anode showed
that carbon dioxide, acetaldehyde and acetic acid had also
been formed, as oxidation products of ether. Based on this
result, Biirker put forward the hypothesis that narecoties had
the same effect in living substance as in the voltameter, and
that the depression of the oxidation process in narcosis depends
on the fact that the narcotie itself appropriates the oxygen.
As, in living tissue, oxygen is activated by oxygen earriers,
the possibility of oxidation of ether even in the cells is not,
indeed, excluded. But under the conditions which obtain in

68 HARVEY SOCIETY

living tissue, it is doubtful whether it really occurs to such
a degree as to reduce the oxidation of respiratory materials
to a noticeable extent. For many of the narcotics, oxidation
in the cells in very unlikely, and in the case of carbon dioxide
it is absolutely excluded.

A third possibility of the interference with oxidation is,
that the narcotic in some way blocks the molecules of oxidiz-
able material, perhaps by a loose chemical fixation, and thus
renders them inaccessible to oxidation, and the oxidation will
thus cease. However, this view also has very little likelihood.
According to this view, we would have to presuppose that
the narcotics, which in themselves present substances with
very heterogeneous chemical properties, were also able to block
very diversified substances; for in non-oxidative catabolism,
such as occurs in narcosis, manifold products arise with very
different chemical properties. We would have to assume that
all these different substances can be prevented from oxidation
by all the different narcotics. We cannot readily have recourse
to such an assumption.

Finally, there remains one more possibility to be considered.
It might be assumed that the narcotic renders the oxygen
carriers incapable of activating the oxygen, so that the ox-
dizable materials could no longer be oxidized and decompo-
sition would proceed only in non-oxidative form. This view
seems to me the most probable, as we have inorganic analogies
for it. The colloidal solutions of metals, for instance platinum
solution, can, as Bredig has shown, be prevented from acting as
oxygen carriers by diverse chemical substances, such as cor-
rosive sublimate, hydrogen sulphide, hydrocyanic acid, ete.
‘‘Paralyses,’’ or depressions, are produced in this way, which
correspond to a great extent with the depressions of living
cells. If I therefore form the hypothesis that narcotics, in
an analogous way, render the oxygen carriers in living tissues
incapable of carrying oxygen, all the facts of narcosis find
a simple mechanical explanation.

But still more, the possibility is also given here to combine

NARCOSIS 69

the relation between the solubility in lipoids and narcotic
action, discovered by Overton and Meyer, with the facts
already given concerning the influence of narcotics on ox1-
dation processes. The fact that the lipoid solubility of a sub-
stance primarily determines the degree of its narcotic action,
shows us that the mechanism which lies at the base of the
symptom complex of narcosis must be associated in some way
with lipoids. We have seen that this mechanism consists in
an inhibition of oxidations, and it is highly probable that this
comes about through a paralysis of the oxygen carriers. It is
quite natural to assume that the oxygen carriers, whose chemi-
cal nature is still entirely unknown to us, stand in some close
relation to the lipoids, that they are perhaps themselves of
lipoid nature, or that they are attached as specific atom groups
to lipoid molecules. By this assumption the relations dis-
covered by Hang Meyer and Overton and the facts shown by
us, that narcosis depends on acute asphyxia, would be com-
bined in a natural manner. Both facts would mutually com-
plete each other, and the result would be a further elucidation
of the mechanism of narcosis.

However, I wish to emphasize, again, that the conception
regarding the nature of inhibition of oxygen metabolism in
narcosis is of a purely hypothetical character. It is only an
established fact that narcotics induce an acute asphyxia of
the cells. Herein is the essence of narcosis.

If we are satisfied, for the present, with this knowledge and
put the question of the particular mechanism of the asphyxia
to one side, the mere fact that narcotics inhibit oxidation
processes will in itself guard us from many false conceptions
in regard to narcosis. The knowledge of this fact has some
significance also for the practical use of narcosis.

Let us ask, first, what we narcotize when we induce narcosis
in man by inhalation of ether or chloroform. All tissues
of the body are not affected equally by any means. Even
if it is assumed that the blood carries the narcotic to all
the tissues in nearly the same concentration, the different tis-

70 HARVEY SOCIETY

sues are influenced to a very different extent by the narcotic.
When the ganglion cells are already completely depressed, the
nerve fibres and muscles still show no sign of narcosis. The
ganglion ceils of the brain, and especially those of the cere-
bral cortex, are most readily affected in their specific functions
by narcotics. Thus, if we induce so-called ‘‘ general ’’ anes-
thesia by ether or chloroform narcosis for any operative pur-
pose, we deal in reality only with narcosis of the cerebral cortex.
In this lies the great value of narcosis; for we desire in
narcosis to eliminate conscious sensation, and the acts of con-
sciousness are, as is well known, due to excitation of the
ganglion cells of the cerebral cortex. The ganglion cells of the
cerebral cortex, with their functions intact, are the most valu-
able asset that man possesses. Therefore it is particularly
important to us that nothing shall happen which might injure
them permanently, and we must therefore know the possible
dangers of narcosis, in order to avoid them.

The fact that the ganglion cells of the cerebral cortex lose
their specific functional activity, under the influence of
narcotics, sooner than any other body cells, must, on the
basis of our new data in regard to the relationship of narcosis
and asphyxia, naturally give rise to the idea that they are more
sensitive to asphyxia than any other body eells. That is
actually the fact to a striking extent. Mosso has demonstrated
this in a classic way on man, in whom alone direct studies of
the conditions of the processes of consciousness can be made.
In his experiments on Bertino, he found that a few seconds’
interruption of the supply of oxygen sufficed to produce loss of
consciousness. Bertino had a large defect in his skull over
the frontal lobe, and the cerebral pulsation could be graph-
ically recorded there. The frontal lobe receives its blood
supply from branches of the carotid arteries. When Mosso
compressed these arteries in the neck, so that the cerebral pul-
sation ceased, Bertino lost consciousness in five seconds with-
out having had any premonitory disagreeable sensations.
After releasing the pressure upon the carotid arteries, con-

NARCOSIS 71

sciousness returned at once. This experiment shows how de-
pendent the cells of the cerebral cortex are on their supply
of oxygen, and in how short a time unconsciousness occurs
after complete interruption of this supply. Here we have an
example of a depression rapidly following the withdrawal of
oxygen. The associative workings of our ideas and sensa-
tions, thoughts and feelings can proceed in an undisturbed
manner only when there is complete integrity of the specific
irritability of all the ganglion cells concerned. The slightest
loss of irritability interrupts the orderly play of excitations
and inhibits the activity of consciousness.

From this peculiarity of the cortical cells is the important
requirement derived, long known empirically, that in man
we should employ a light degree of narcosis, just sufficient
to paralyze consciousness. Under such circumstances the de-
pression of the oxidative processes is undoubtedly of very
limited extent, and there is no demonstrable danger of per-
manent injury to the normal brain. When we employ a
deeper narcosis, the danger of rapid and complete asphyxia
of the ganglion cells increases with the depth of the narcosis.
At any rate it ought to be always present in our mind that
the deeper the narcosis the more it inhibits oxidation processes,
and that the ganglion cells of the cerebral cortex are exceed-
ingly sensitive to lack of oxygen. Here we deal with the most
tender and perishable cells of our body.

In this connection I wish, before concluding, to point out
an error that has been handed down from olden times, and
even at present has not been corrected everywhere. It is the
identification of narcosis with sleep.

The origin of this confusion is evident. It is based on the
entirely superficial analogy that both states are characterized
by loss of consciousness. But not every loss of consciousness
is sleep. This confusion, which may have been justified in
earlier times, when both conditions were known only by their
external symptoms, is to-day, when we have penetrated some-
what more deeply into the inner processes of the cells of the

72 HARVEY SOCIETY

cerebral cortex, a grave mistake. Closer consideration will
show this plainly.

What occurs in the neurons of the cerebral cortex during an
act of consciousness? I am far from intending to give here
a detailed analysis of these processes. I wish to emphasize
only a single general fact. Let us conceive a condition of the
cerebral cortex in which the neurons are in metabolic equilib-
rium; that is, in which the two phases of metabolism, the ana-
bolic and catabolic phases, balance each other. We should
have then a state of complete rest, in which no act of con-
sciousness takes place. An act of consciousness ensues only
when the metabolic equilibrium in a chain of associated
neurons is disturbed by an exciting stimulus which causes a
sudden increase of the catabolic phase. Every act of con-
sciousness is the expression of a catabolic disturbance in the
cortical neurons. This is not merely an assumption; it is
shown, among other things, by the fact that even the simplest
conscious process requires the associated co-operation of sev-
eral ganglion-cell stations, and that on the other hand the
nerve fibres which provide for this associated co-operation
conduct no other impulses than catabolic excitation proc-
esses. On this general basis, for all processes of consciousness
there are two possible origins of unconsciousness. Loss of
consciousness will occur either because the ganglion cells are
depressed, so that the external stimuli produce no excitation, or
because exciting stimuli are absent. As we have seen, the
first condition prevails in narcosis; the irritability is so much
depressed that stimulation is ineffective. In sleep, the second
alternative is predominant; the first plays at most the réle of a
predisposing part for the induction of sleep. We sleep, and
determine the moment of going to sleep, by limiting as far
as possible the sensory stimuli, especially the optical. This
state of the utmost exclusion of external stimuli lasts through-
out the entire period of sleep. This is supported to a certain
extent by fatigue, that is, the decrease of irritability, which
the ganglion cells have sustained by the constant action of

NARCOSIS 73

sensory stimuli while awake during the day. A comparison
of the processes which occur in the ganglion cells of the cere-
bral cortex during sleep and during narcosis will show us
plainly how diametrically opposite these are.

During sleep, restitution occurs. The irritability, which
becomes reduced in the course of the day as a result of the
fatiguing action of sensory stimuli, gradually rises again.
The fatigue of the ganglion cells, which, as we know, depends
only on a relative lack of oxygen, becomes completely dispelled.
The supply of oxygen, which during constant activity was not
quite sufficient to keep irritability at its maximum, is, after
the cessation of functional demands, fully sufficient to banish
the fatigue. In short, during sleep, restoration occurs princi-
pally by the action of oxygen. In the morning the ganglion
cells are refreshed and possess their full capacity for work.

How different is narcosis! In narcosis there is, on the con-
trary, as we have seen, a depression of the oxidation processes.
The experiments showed that even with a free supply of
oxygen a fatigued ganglion cell did not recover at all during
narcosis. There occurs, rather, a gradual asphyxia, and, al-
though this process is only developed to a small extent in light
narcosis, still it presents just the reverse of that which sleep
brings to the ganglion cells. In the one case, recovery from
fatigue by oxidation; in the other, prevention of restitution
by inhibition of the oxidation process. There can be no con-
fusion between sleep and narcosis.

If we use narcotics to induce sleep, we must always bear in
mind that no true sleep occurs as long as the narcosis of the
cortex lasts. We can speak of ‘‘ hypnotics,’’ or ‘‘ remedies for
sleep’’ (Schlafmittel), only in the sense that, when there
is constant excitation of the ganglion cells, they reduce irrita-
bility and induce a greater degree of depression, so that true
sleep may take place as the narcosis passes off. In that sense
a hypnotic may prove beneficial in the hands of the physician,
and when used sparingly. The physician must, however, never
forget that not the entire period of unconsciousness which fol-

74 HARVEY SOCIETY

lows the use of the hypnotic is true sleep, but that at first it is,
rather, a depression, the injurious effects of which will mani-
fest themselves when the hypnotic is used for a longer period.

Ladies and Gentlemen: I am at the end of my lecture. The
facts which I have stated take us, I believe, a step forward in
the analysis of narcosis. They show us the general nature of
the process, which is merely one of the great group of depres-
sive actions which depend on a disturbance of the oxygen
metabolism. They open, however, at the same time, a number
of new questions. The previously mentioned hypothesis con-
cerning the method by which narcotics inhibit the process of
oxidation shows us the direction in which these questions lie.
It may serve us as a guide for the present. The further
analysis of the process will principally have to determine the
nature of the transmission of oxygen and in what way this is
affected by the narcotic. The experiences of modern physical
chemistry will be of great help to us in the study of this ques-
tion. I may, however, take this opportunity of warning
against the misuse of physical chemistry in the explanation of
biological facts; and this the more, since this misuse, which
has grown with the development of that science, is already
beginning to arouse in the minds of many biologists a strong
distrust of the value of physical chemistry in the analysis of
biological processes. It is frequently believed that a biological
process is explained when the terminology and certain catch-
words, I might almost say the scientific ‘‘ jargon,’’ of physical
chemistry have been applied to biological relations. There has
been recently, for example, a great misuse of the word
‘‘eolloidal process.’? There is positively nothing gained by it
when a biological phenomenon (for instance, excitation or
depression) is designated as colloidal process. This is neither
correct nor incorrect; it says nothing. That the living tissues
contain various colloid substances, and that these colloids un-
dergo alterations in the course of the vital processes, has long
been known. We wish, however, to know what it is that
happens to the colloids, which of their properties are altered

NARCOSIS 75

and how these changes are incorporated into the machinery
of the cell. For this purpose patient and careful analysis is
required, and not the introduction of mere catch-words. The
methods and results of physical chemistry give us very valu-
able material for such analysis; but it would be very one-sided
to consider the methods of physical chemistry only. The
methods and results of chemistry, physics, and microscopical
research must be employed, as well as those of physical chem-
istry. In short, every method must be employed which will
bring us a step further. That alone can be the general prin-
ciple of all physiological research, and this principle will also
lead up to new knowledge in the investigation of narcosis.

ON FREUD’S PSYCHO-ANALYTIC METHOD
AND ITS EVOLUTION *

PROF. JAMES J. PUTNAM
Harvard University

HE subject of psycho-analysis, on which your long-hon-
ored president has invited me to speak, is one that deals
with serious and difficult problems. I shall be glad if I can
throw a flashlight on them here and there, and in so doimg I
shall try to answer some of the questions which have most
frequently been asked me concerning the subjects in hand.
Do not suppose that I shall pretend to give directions such
as could enable any physician to put this method into prac-
tice. On the contrary, I beg you to regard it as a matter
for congratulation that the leaders in this movement have a
strong sense of the need of careful training and high stand-
ards on the part of those who desire to join their ranks. I have
recently returned from a trip abroad, where I made the per-
sonal acquaintance of quite a number of the more prominent
psycho-analysts, attended their congress, and was able to learn
a great deal about the details of their mode of work. I came
away strongly impressed with the fact of the recognition on
their part of the importance of their task and that this recog-
nition had had a good effect on the mental attitude of the
workers, many of whom are still young and full of promise.
These men seemed to me, for the most part, strikingly
eager, earnest, and sincere. ‘‘ Sie haben gelernt ein Stick
Wahrheit zu ertragen,’’ said Freud to some of us when these
facts were under comment. I learned to my surprise and
interest that the greater number of the investigators had
subjected themselves, more or less systematically, to the same
sort of searching character-analysis to which their patients

* Delivered November 11, 1911.
76

FREUD’S PSYCHO-ANALYTIC METHOD ve

were being subjected at their hands. It is fast getting to be
felt that an initiation of this sort is an almost indispensable
condition of good work; and for this important reason: The
main thesis of the supporters of these new doctrines—which
are at bottom old doctrines, rearranged and re-emphasized, for
psycho-analysis is largely an accentuated phase of education—
is that most of the emotional disorders to which we give the
name of psychoneuroses arise largely from an instinctive self-
concealment, and concealment of one’s self from others; that
is, from an unwillingness or an inability to see or look at
all the facts that should be seen, respecting one’s own ten-
dencies and motives, as the basis for the control of feeling,
thought, and action. Recognizing this principle, these physi-
cians have seen that so long as their own lives, too, are par-
tially on a false basis, so long as they also are self-concealed,
they cannot do justice to their patients, either in the way of
appreciation or of criticism. Obviously, a person ridden by
prejudices that he does not recognize cannot do justice to
another person in a like state; one is reminded of the simile
of the ‘‘ beam ’’ and the ‘‘ mote.’’ It is, therefore, I repeat, a
matter for congratulation that the need of preparation for
these tasks is being taken seriously, and the assertion is justi-
fiable that the introduction of this specialty is likely to make
better men, in every sense, as well of the physicians who prac-
tise it as of the patients whom they treat.

But while no man, however able, can without long study
master the details of this method, every man who would be
liberal or scientific can and should master its principles and
give the movement his generous sympathy and support.

What is psycho-analysis, and what, in general, are its aims?
Psycho-analysis is a method of investigating and treating ner-
vous invalidism and (incidentally) faults of character, which
owes its strength to the fact that it searches and studies in de-
tail, so far as this is practicable, all the significant experiences
through which the patient to be treated has passed, and the
motives and impulses which have animated him at psychologic-

78 HARVEY SOCIETY

ally important moments of his life, even since his earliest child-
hood. In doing this it discovers, not, indeed, all the causes
of the disorder from which he suffers, but a large number of
important partial causes, and thus prepares the way for the
influences tending toward recovery. This definition is, I think,
substantially correct, but it needs some explanation, amplifica-
tion, and qualification.

First, it is not strictly true to say that the attempt is made,
during a psycho-analytic treatment, to pass in review all of
the important motives and impulses, or even all of the kinds
of motives and impulses, which had animated the mind of the
person who subjects himself to this treatment, but, strictly
speaking, only a certain class of them,—those, namely, that
were originally based on emotions which had been repressed
because they were painful or seemed out of harmony with the
chosen plan of life, but which, in spite of all repression, had
remained as active causes of serious mischief. It does not
systematically deal with those motives and impulses which
may be designated as aspirations and ideals, derived, as I
believe, from the essential endowment of the spiritual nature
by which every man is animated and which is to be regarded
as an independent, primary, creative force. Psycho-analysis
does not, in other words, pretend to take the place of philo-
sophic teaching; but it does help, even without claiming to
do so, to give such teaching a better chance to make itself
effective.

On the other hand, it is not just to characterize psycho-
analysis solely as a therapeutic measure. In proportion as the
psycho-analytic movement has developed toward maturity, it
has shown itself able to make scientific contributions of great
value to psychiatry,t psychology, mythology, philology, so-
ciology, as well as to education and to prophylaxis. In other

*The value of Jung’s argument for ranging Kripelin’s dementia
precox, together with many symptom-complexes classified by Janet
as psychasthenia, under the psychological category of the introver-
sions, is now generally conceded.

FREUD’S PSYCHO-ANALYTIC METHOD 79

words, these investigations bring support to every research
which deals with the inward and the outward manifestations
of human effort and mental evolution, while at the same time
they draw important aid from all these inquiries into the
psychology of the human race, for the benefit of the single
human life.

The practical aim of this method is to enable persons who
are hampered by nervous symptoms and faults of character
to make themselves more efficient members of society, by
teaching them to shake themselves free from the subtle web
of delusive, misleading, half-unconscious ideas and feelings
by which they are bound and blinded as if through the influ-
ence of an evil spell. Such persons—and in some measure
the statement is true of all persons—have to learn that they
are responsible, not only for the visible, but also for the hidden
portions of themselves, and that, hard as the task may be,
they should learn to know themselves thoroughly in this sense.
For it is the whole of ourselves that acts, and we are responsi-
ble for the supervision of the unseen as well as for the obvious
factors that are at work. The moon may be only half illumi-
nated and half visible, but the invisible half goes on, none
the less, exerting its full share of influence on the motion of
the tides and earth.

Some patients may learn to override or sidetrack their
troubles and can be helped by various means to do so. These
other means are, however, not to be compared, for power of
accomplishment or permanency of result, with that of which
I now speak to you.

It is difficult to see why any broad-minded person should
refuse to recognize, on theoretic grounds at least, the value of
the self-knowledge here alluded to, especially when the treat-

ment of the more serious forms of psychoneurotic illnesses is
at stake. These more serious forms are very numerous and the
causes of enormous suffering. Difficult and doubtful of issue
as the treatment of them is, the method here discussed holds
out a new and vital hope.

80 HARVEY SOCIETY

It would obviously be impossible to offer you anything ap-
proaching to an adequate account of the means by which it
is sought to discover, for each individual case, the particular
facts and tendencies from which the particular symptoms * that
are present may have sprung. It must be enough to assert the
fact which Freud established, that each person’s memory, if
allowed and encouraged to wander, uninhibited by resistances
and repressions, may usually be counted upon to furnish the
information that is needed. Where this is insufficient, two
other plans may be adopted, one of which, indeed, comes largely
into play in every case. These two methods are, first, the use
of word-associations, the value of which Dr. Jung, of Zurich,
has done so much to establish, and, next, the study of dreams.

The significance of the word-association method, stated in
briefest terms, is that it serves as a sort of concentrated con-
versation. The patient, answering at random as he should do,
instinetively lets go,* for the time being, of the reins which
he ordinarily holds tight over his inmost thoughts, and allows
glimpses into the mental processes which it is of the utmost
importance that he should know yet which constantly tend to
elude his attempt to seize them. Further inquiries and associa-
tions may, then, if necessary, proceed from such beginnings.

The elucidation of the means by which the interpretation
of dreams may be successfully carried on, and a path thereby
opened into the inner chambers of the mental life, is one of
Freud’s contributions which well deserves being designated as
a mark of genius. Whatever differences there may be between
the conscious lives of different individuals, in our repressed
and unconscious lives we are all very much alike—not, indeed,

* Such symptoms are not to be regarded as haphazard and unlucky
but meaningless signs of breaking down on the part of the nervous
system; they are, rather, real and significant reactions, dumb ex-
pressions of both terms of very deep and vital inner conflicts, but
under the form of compromises between instinetive desire or eravings
and instinetive denials of these cravings.

°Tf the reins of thought and emotion are not relaxed this fact
too will become evident.

FREUD’S PSYCHO-ANALYTIC METHOD 81

in detail, but as regards the principles in accordance with which
we are constructed.

Just as we speak the same verbal language, so we speak, at
bottom, the same dream language, and can learn to make the
meaning of our dreams clear to others and to ourselves. It
eannot be too often represented that the disharmony between
the conscious and the unconscious portions of our lives, which
is sometimes productive of so much misery, ought not to exist.
Every one recognizes this after a fashion, and tries, instinct-
ively, but, as a rule, without success, to overcome the dishar-
mony by finding some sort of outlet for the repressed—and
usually childish—feelings which his conscious intelligence will
not tolerate. But this is not enough. If he would really
overcome the disharmony, he must meet the situation face to
face, and the study of his dreams, in which his repressed
thoughts are represented in caricature and in picture lan-
guage, is perhaps the best means of obtaining clues to the in-
formation which he seeks.

These hidden portions of our lives must be thought of as
seeking to make themselves felt in action though not in words.
Ordinarily, we keep them, like the evil spirits in Pandora’s
box, under pretty strong lock and key. At night, however,
the locks are loosened, and our repressed emotions succeed in
finding their way to the theatre-stage of consciousness. Even
then, the thoughts which arise are not allowed to become too
evident, but are concealed beneath picturesque symbolisms
and disguises.

It is a very interesting fact that, as each new person comes
into the world and begins his life of dreams, he adopts forms
of symbolism analogous to those which have been in use since
even semi-civilized life began. The various animals with
which our childhood was familiar come forward to play the
role of animal-passions; the rapidly moving trains typify our
hurrying emotions. And so, too, still or moving water, the
rooms or buildings in. which we like to place ourselves, the
bare or varied landscapes, and many a symbol more, are all

82 HARVEY SOCIETY

utilized as elements of a picture-language which is almost as
well defined as that indicated by the rebuses of the child, or
the hieroglyphs of the Egyptians, or the mythology of the
ancient Greeks.

So full of meaning are these signs that no dream carries its
true, much less its whole, significance on its face; no item, no
obvious omission even, is without its bearing; hardly a feature
or character is to be found that is not of even multiple value.
The general proposition has been laid down—and certainly
with good reason—that every dream represents the fulfilment
of an unconscious wish. No one would doubt that this state-
ment is true of the day-dreams of childhood, and when for
‘* wishes’? we read ‘‘ partial ’’ or ‘‘ temporary ’’ wishes, and
learn by self-study what these partial wishes are, it is found
in the dreams which appear so terrifying, the wish is con-
cealed behind an attempt to repress it, just as the partial
wishes of our waking moments are often concealed behind the
disguise of fears, a phenomenon very characteristic of the
phobias of neurotic patients. Persons unfamiliar with the in-
terpretation of dreams often deny this tendency, and point
out that their dreams are nothing but jumbled representa-
tions of some trivial happenings of the day before. It is true
that every dream takes the happenings of the day before as
materials out of which to construct its apparent story. These
trivial experiences are utilizable, partly because of their ana-
logical bearings, partly because they are still conveniently
available for the memory and yet not fully woven into any
other of the various complexes which our emotions tend to man-
ufacture. In utilizing these experiences the dreamer does
what any person might do who wished to tell a story while
sitting at the dinner-table with his friends. Assuming that
he desired to describe a journey he had taken, he might select
a salt-cellar to stand for a castle that he had seen, a fork for
one road, a spoon for another road, a plate for a pond or
lake, ete. But behind these hastily chosen symbols, there
would be a connected story; and in the same way, behind

FREUD’S PSYCHO-ANALYTIC METHOD 83

the trivial details which make the outward framework of the
dream there is a connected story, which, indeed, reaches, in
layer after layer, back into the dreamer’s earlier life and
even into his childhood. For in every mental act the whole
personality of the individual comes into play, although in each
act certain elements of the personality are illustrated far more
than all the rest. Of course, it need hardly be said that the
analogy between the forks and spoons and the apparently trivial
incidents of the day previous to the dream-night is by no
means a complete one. Unimportant as the real incidents may
seem, they are often full of meaning, which, however, only an
expert analysis can reveal. Each dream, then, furnishes, to
the expert, and to the patient, a path into the inmost recesses
of the patient’s life, better than any other means could furnish.

As regards the therapeutic value of the psycho-analytic
method, it is almost needless to say that there are many cases
that baffle every treatment, not excepting that by psycho-analy-
sis, and that this method has its special limitations. The pa-
tient, to be treated with success, must be reasonably young,
reasonably intelligent, and able to give a large amount of
continuous time to the investigation. His outlook as regards
conditions of life must be reasonably favorable, or else he must
have the capacity for idealization such as will enable him
to override outward misfortunes, and to face existing condi-
tions cheerfully. He must want to get well, and not count
on his illness as giving him gratifications or advantages which
he is unwilling to sacrifice, even for better health. Then,

‘Perhaps the two most important sets of facts to look for in the
interpretation of a dream are: (1) the multiple and multiform special
reminiscences suggested or symbolized by each thing, circumstance,
or relation; (2) the various “ movements” or “ tendencies” hinted
at. Somebody (the dreamer) is doing or experiencing something
or having something done to him. That something is of deeply
personal, perhaps infantile significance. Knowledge and keen in-
sight must see through all disguises and determine what that something
is. Not infrequently the apparent data must be absolutely reversed
in order to be rightly understood.

84 HARVEY SOCIETY

of course, some sorts of symptoms are less curable than others,

The length of time sometimes required for successful treat-
ments has often been the subject of comment. But in fact
it is a great gain to have a method capable, even in a long
time, of producing fairly good results. Any one who thinks
about the matter must realize that it is extremely difficult to
make any considerable change in one’s own character or
habits. Our good qualities, as well as our faults, are deeply
founded. Both have their roots in the experiences of infancy
or in the reactions of childhood, and if we would help our-
selves to the best purpose we must get back, in knowledge,
feeling and imagination, to the conditions under which the
deviations from the normal first began. To accomplish this
takes time and patience, though the task is full of interest.

It would not be justifiable to assert that the psycho-analytic
treatment can accomplish such results as are claimed for it
if we could not assert at the same time that the investigations
based on psycho-analytie studies have thrown new and im-
portant light on the nature of the disorders with which the
method deals. Without this light, a rational, causal treat-
ment of these affections would be as far out of our reach to-
day as it was in the last century, and we should still be throw-
ing ourselves against the rocks and reefs of this great prob-
lem, chipping off a bit of stone here and there, but making
no consistent progress.

The splendid insights of Charcot, and the remarkable re-
searches of Pierre Janet with regard to the phenomena of
automatism and the mental state of hysterical patients, brought
the first real illumination into this obscurity,—an obscurity
greater than we then could realize. The lines on which Freud
began to work were somewhat parallel to Janet’s in that both
of these great leaders quickly learned to recognize the im-
portance of the apparently forgotten and seemingly dead ex-
periences of the invalid, and showed that they might still
be acting as motive forces in the affairs of the present mo-
ment. Freud soon arrived, however, at the important con-

FREUD’S PSYCHO-ANALYTIC METHOD 85

clusion that it is not enough to know single incidents of the
past life, let them be never so grave, but that the whole life
must be drawn upon and made to yield its entire history,
and he proved that when the whole life is exhaustively studied
on this plan it is possible to explain the symptoms of illness
as largely referable to demonstrable influences operating since
birth, and thus to get on without making such large drafts
on ‘‘ inherited tendencies,’’ of which we know so little, as the
principal causal factor. Then it gradually became clearer that
the gaze of the investigator must be directed with ever greater
insistence towards the very earliest years of life as the time
when the seeds of mischief are sown—that marvellous period
when tendencies are established and paths of least resistance
are laid down, which may give a set or bias to all the years
to come, and cause the child’s mind to become sensitized, as
if through a process of anaphylaxis, to special influences which
may be brought to bear later, though perhaps not strongly
until a much later period. The life-history of the normal
child became, naturally, the next object of these ever-widening
studies, and then the attention of a special group of investi-
gators was turned upon the childhood-history of the races
of men, as described in sagas and in myths. Even the his-
tory of criminology and of sexual perversion—already mapped
out in part through the studies of many men, but now for
the first time made to yield its true lessons—has been largely
drawn upon, for the sake of discovering and illustrating the
nature of the dangers with which the early years of every
child are more or less beset.

One instructive method of getting an idea of what passes
in the child’s mind, of the difficulties which he encounters and
the means that he takes to meet them, is to observe carefully
how we ourselves deal with corresponding situations: Every
one who is accustomed to scrutinize his own thoughts and
conduct must realize that he is often tempted to put out of
sight what he does not like to think of; to seek enjoyment

86 HARVEY SOCIETY

instead of doing work, and, in general terms, to live on a
mental plane lower than his best.

Most of the temptations by which we are beset might be
classified under one or the other of two headings; namely,
the desire for gratifications or undue self-indulgences of a
relatively personal sort, and the desire for gratifications im-
plying the approbation, admiration or the attention of others,
if only through subserviency or domination. I am not now
concerned to prove the prevalence of these temptations or to
deny that we may utilize them to our profit, but only to call
attention to the fact that a more or less universal and some-
times irresistible tendency exists, which impels us, on the
one hand, to secure these gratifications, and, on the other
hand, to protect ourselves from self-reproach for so doing.
In the interest of these two motives, which are, of course,
comparatively rarely conscious motives, we cloak our cravings
under forms which tend to make them seem justifiable and
even admirable.

Every thoughtful person is more or less aware,—though
it is only the well-trained or unusually discriminating ob-
server who can thoroughly appreciate the fact,—that an ele-
ment of craving for self-gratification may lie hidden under
the guise of anger, prejudice, fear, jealousy, depression, de-
sire for self-destruction, ‘‘ over-conscientiousness,’’? and the
wish to inflict or to suffer pain. It is equally true that un-
der the form of restlessness, or that of a sense of incom-
petency, we symbolize the hidden conflicts which cover our
desire to escape from ourselves, or our incapacity to under-
stand or unwillingness to face the full meaning of our emo-
tional desires.

Those of us who eall ourselves ‘‘ well ’’ owe it to those who
are forced to call themselves ‘‘ sick ’’ to study the true nature
of these innumerable faults of character. When this is done,
it is discovered that these faults deserve the name of ‘* symp-
toms,’’ and that, like symptoms, they are disguises and com-

FREUD’S PSYCHO-ANALYTIC METHOD 87

promises, concealing painful conflicts that may date back to
the experiences of infancy.

It must be remembered that between the period of birth
and the later years of childhood each individual recapitulates
in a measure the history of civilization. The parent and the
community who see in the infant not so much what he is as
the promise of what he is to be, make little of those qualities
in him which would be considered as intolerable if judged
by our adult standards. But these qualities exist, neverthe-
less, and the growing child to whom they are transmitted must
deal with them as he is best able, whether by gradually modi-
fying them for the better, or by shrinking from them in dis-
gust, or by continuing to indulge himself in them in con-
cealed forms. One fact must never be forgotten, namely, that
each child comes into the world with one mission which he can-
not overlook or delegate and which he shares in common with
every living thing,—the mission of preparing to do his part
in the perpetuation of his race. For the sake of the establish-
ment of the great function on which this depends, he is pro-
vided, in infancy, with a considerable number of capacities
in the way of sense-gratification and with ample means of
indulging them, which, however, he must eliminate as he grows
older or preserve at his risk. But this risk the infant does
not see, and before the time comes when he can see it he may
have found himself drawn into paths of least resistance, lead-
ing both to pleasure and to pain, from which it will be diffi-
cult for him to escape. There is, then, no easy course left open
for him but to repress his desires for these indulgences, just
so far as may be necessary for concealing them from him-
self, while at the same time he invents substitutes and com-
promises in which the indulgences are continued under a new
form. Yet, unfortunately, the adoption of such compromises
is equivalent to laying a foundation for defects of character
or for symptoms of obstinate forms of nervous illness, as the
case may be.

Clear memories of these earliest years of childhood rarely

88 HARVEY SOCIETY

are retained. Yet some individuals retain very much more
than others, and this fact, taken in connection with the evi-
dence furnished by dreams, by a few careful observations of
young children, and by the memories of patients trained under
the psycho-analytic treatment, leads to the conclusion that a
large part of the apparent forgetting is based really on
repression.

From the standpoint of the next later period many of the
details of infancy are unpleasant to recall. One is reminded
of the Mohammedan cadi who, when asked about the early
(Christian) history of his town, replied: ‘‘ God only knows
the amount of dirt and confusion that the infidels may have
eaten before the coming of the sword of Islam. It were un-
profitable for us to inquire into it.’’>

The period of childhood, though it contains many elements
of happiness, which are usually accentuated and continued
by the child’s delightful power of grief-compensating fancy
as exhibited in day-dreams, contains also many elements of
suffering. The child’s fears—of the dark, of storms, of mys-
tery and power in a thousand forms—have been explained °
as due to the organic memories of his pre-human ancestry;
to the recognition of the contrast between his weakness and
the bigness and strength of those about him or (in a religious
and philosophic sense) the vastness of his own inexhaustible
possibilities. There is nothing to urge against these explana-
tions, but they cannot be regarded as covering the ground.
The young child is at least partly like the older child and
the adult, and fear, with them, cannot be studied as apart
from the desire which so often underlies it. Like Scott’s aged
harper, we all ‘‘wish, yet fear,’? and frequently the wish
becomes gradually repressed, and the fear alone remains. We
all ‘‘ fear ’’ those most whose approbation we most ‘‘ wish,”’
and fear the tests in which we most long to succeed. The

* Cited in James’s “ Psychology,” vol. ii.

°Of. Pres. G. Stanley Hall’s paper: Study of Fears. Am. Jour.
Psychol., January, 1897, vol. viii, pp. 147-249.

FREUD’S PSYCHO-ANALYTIC METHOD 89

child, with his splendid fancy and his intensified training in
the symbolism of fairy-tales, loves to play with these fears and
wishes. The dark stands for delicious, as well as alarming,
mysteries, and beyond these there is also always the longed-
for chance of the pleasure of re-discovering himself in his
mother’s arms."

The strength of the child’s tendency to follow pleasurable
paths of least resistance may be vastly diminished, or, on the
other hand, vastly increased, by the fact that the immense
forces of social custom, by prescribing what should be done,
help to deprive the child of his own sense of responsibility,
while at the same time they seem to relieve the parent from
the necessity of seeking to discover what is really passing in
the child’s mind. We talk of independence, but, in fact, the
community is almost fanatic in its demand for conformity.
The key to the solution of these difficulties must be sought,
not primarily in the education of the younger generation, but
in that of the older. Jt is with the lack of knowledge on
the part of the parents, and the disregard by physicians of
the need of acquiring and imparting adequate information
on these subjects, that the reform must deal. There can be
no doubt but that our social and ethical customs, which rep-
resent the filtered experience and wisdom of the race, are of
immense value. But the ends which they mainly seek and
the methods which they follow are not chosen with reference
to the needs of the neurotic child. These points are of such
importance that an attempt must be made to state them some-
what more fully, even at the risk of exciting misunderstand-
ings.

The family influences under which most healthy-minded
children grow up are, of course, eminently beneficial, and this
is no place for discussing their shortcomings.

But the fact remains that nervous invalidism is extremely
common; that it is closely bound up with social relationships

"This pleasure has a philosophie bearing to which I cannot here

allude.

90 HARVEY SOCIETY

of varied sorts; and that the school in which the child gets
his first introduction to these relationships is the home.

One cause of unhappiness in married life, for example, is
the inability on the part of the husband or the wife to adopt
the new duties with a whole heart. This inhibition is often
due, in part, to the craving, established in childhood, for an
undue continuance of the parental ties, with all that they
imply; an unconquerable homesickness, which often cannot be
put into words or recognized in its own form, overrules the
new interests which ought to be supreme.

These are facts of common knowledge, but under the light
of this new movement they have been studied with a thor-
oughness previously impossible, and have been correlated with
others of a kindred sort, with the result of immensely increas-
ing their significance.

It should not be forgotten that father and mother are not
only objects of admiration, imitation and veneration to the
growing child, but that they stand likewise to him as man and
woman, and that, as such, they are in a position of peculiar
responsibility and may be centres of peculiar harm.

I am not undertaking here to lay down rules for conduct,
nor even to assert that although, on the whole, frankness and
a well-guarded, thoroughly wholesome intimacy between pa-
rents and children is eminently desirable, it is very undesirable
to break down all barriers of restraint between them. The
evolution of modesty and of a certain amount of personal re-
serve needs to be safeguarded, even at some risk.

Real knowledge with respect to these complex matters
should be sought, but it is hard to get and its advent is not
to be awaited with impatience, or its acquisition as the basis
of judgment and conduct assumed on insufficient grounds.

Another point of importance is that the dawning self-
consciousness of the infant represents him to himself, not
definitely and distinctively as ‘‘ boy ’’ or ‘‘ girl,’’? but as a
being standing in relations of dependence to other and more
powerful beings, whose characteristics he does not differentiate

FREUD’S PSYCHO-ANALYTIC METHOD 91

from the sex-standpoint. The significance of this statement
will be understood without difficulty by any one who will con-
sult carefully even his own experience and observation. Every
one must be aware that we all have some traits which are com-
monly designated as masculine, and others designated as
feminine, and that the evolution which best marks social prog-
ress is based on the working out, in the case of each person,
of capacities related to both of these sorts of traits. The at-
traction which persons of our own sex have for us is of great
value as leading to friendships which may become exceedingly
warm without ceasing to be eminently desirable. It is, how-
ever, well known that such friendships may develop into rela-
tionships which are eminently undesirable and a-social, and
even, in the case of men, of a kind that would be called
criminal. Between these two extremes, tendencies are to be
observed, or are to be detected through careful study in a
given case, which may lead to hidden conflicts and to distress-
ing nervous symptoms. Good observers have shown it to be
true that just as, to a certain degree, many men prefer the
society of their fellows at the club to that of their wives and
families at home, so, in a much deeper sense, nervous invalids
often waver between attractions which would lead them in
the direction of the most wholesome and useful relationships,
either of marriage or friendship, and those which have an un-
wholesome tendency. The objectionable forms of these ten-
dencies, if not created, are, at least, accentuated, by the over-
strong, or, rather, by the slightly abnormal attachment of the
infant to the father on the one hand or to the mother on the
other. It is true, at the same time, that there are probably
also deeper influences at work, dependent on some tendency
which each person brings into the world, but of the exact na-
ture of these latter influences it would be premature to speak.
The subtlety of the danger here noted is what gives it its
effective power, for what could seem to be freer from danger
than parental love? Obviously nothing, when this love is
fortified by wisdom and knowledge. In fact, however, it hap-

92 HARVEY SOCIETY

pens but too often that, either because the child is too imma-
ture in his manifestations of affection or because the parents
retain too much of their own childishness, that which should
be a source of infinite happiness and should lead the child
towards independence and self-reliance becomes, instead, an
opportunity for the growth of unwise emotion and a weaken-
ing tendency to imitation and dependence.

A careful study of the child’s personal gratifications has
shown that a portion of the earliest and strongest of them,
which, for the most part, have to be repressed later, are re-
lated, first, to the satisfying of hunger, then to the securing
of certain specific pleasures, such as the massive feelings of
warm contact (during the diaper period), and those due to
the excitation of the orifices of the body, especially the mouth,
the urethra and the anus. To the child these sources of
gratification stand at first, both morally and from the social
standpoint, on an equal footing. He is unaware that he is
likely to be subjected to serious temptations with reference
to some of them; he does not know that his reaction to them
may decide whether he is to become a being capable of recog-
nizing that his best freedom is to be found in a willingness
to devote himself to the welfare of the social whole, or whether
self-indulgence is to be his ruling motive. The child who con-
tinues too long to suck his thumb, or wet his bed, or who finds
undue fascination in the emptying of the bladder and the
rectum, or detects a mysterious significance in these events,
may be acquiring a tendency to prolong bodily indulgences
which ought to be outgrown, and laying the foundations for
other personal gratifications of more subtle, more distinct-
ively mental, and, socially, of more disastrous sorts. Mastur-
bation, of course, although accused of dangers which do not
belong to it, stands high among these over-indulgences of a
purely personal, auto-erotie sort.

Freud has been criticised for making too much of the
sexual element in these problems; for seeing sexuality where
it does not exist. But is this eriticism just? The number of

FREUD’S PSYCHO-ANALYTIC METHOD 93

those who think so is growing daily less, as sober judgment
and knowledge of the facts come better into play. Think with
what inconceivable, with what seemingly unwarrantable te-
nacity, nature, bent on the perpetuation of the life, both of
the individual and the race, has safeguarded the function on
which this depends. Many plants if starving will flower all
the more abundantly, as if in order that their descendants
at least may live. Think how every novel, every drama, is
founded on some aspect of the sex problem. Is not the truth
rather that these problems are felt to be of such enormous
importance that we ought perhaps to shrink from touching
them just as we might shrink from handling bombs charged
with dynamite of high explosive power? And yet, is this
true? Is not the dynamite to a great extent the figment of
our imaginations, filled with repressed memories which we have
not known how to study, but whose rumblings we have all
vaguely felt within us?

This, or something like it, was, at any rate, the feeling which
led Professor Freud long ago to enlist for his campaign, and
determined him to risk everything for the laying bare of these
long-neglected facts. He might have said to himself, whether
he did or not, that he would take the great studies of human
character, like those by George Eliot, or by Meredith, and
would go on where these writers stopped, striving, in the spirit
of the novelist turned man of science, to discover the processes
of childhood through which the strong, deep tendencies which
they describe came into being. Those who oppose this move-
ment out of unwillingness to discuss the sexual life, are not
only declining to be scientific and impartial (since to the scien- -
tific person nothing is in itself disgusting or unworthy of con-
sideration), but also are rendering it harder for patients to
get well, by stamping as indecent their attempts to gain a true
knowledge of themselves.

I should like to eall your attention to the fact that in the
beginning it may be only a slight over-accentuation of an infan-
tile tendency that makes the difference between the promise

94 HARVEY SOCIETY

of health and the promise of invalidism. But when the lines
which enclose the angle of deviation have become extended,
as the child grows up to manhood, the actual distance becomes
immense. One is reminded, here, of Jean Ingelow’s poem,
‘* Divided,’’ and, still more, of George Eliot’s great study of
Tito, in ‘‘ Romola.’’ Charming, handsome, kindly, scholarly,
Tito seemed, as a youth, to have all possible good qualities, save
that he possessed, or was possessed by, an apparently trifling
tendency to self-indulgence, or selfishness, of the concealed,
insistent, infantile type. This was never very prominent, but
it was always present and always irresistible, and it made
him in the end a fiend. And yet, from the psycho-analytic
standpoint, Tito’s was a curable case. At any moment, up
to the very last, if he could have been aided to penetrate the
history of his own life, and thereby to see at one glance the
system of interlocking forces representing his still active ten-
dencies of childhood and their logical outcome in his present
acts,—as one looks through a transparent model of the brain-
tracts,—he might perhaps have undone the mischief. For a
man’s emotional and mental past, even if of his infancy, never
dies; it is always present and active, and represents a force
which is always susceptible, theoretically at least, of modifica-
tion or neutralization, in the interest of progress.®

There are several advantages in classifying, as Freud
has been criticised for doing, the many and varied tendencies
of which novelists write, as sex-tendencies. But perhaps the
most important advantage is the practical one that it enables
the physician, on suitable occasions, to point out the direction
in which a given act or thought, conceivably innocent in itself,
may lead.

“Strictly speaking, we never obliterate the memories of our past
experiences, and even to wish to do so would be in accord with the
spirit of an Oriental rather than of a Christian philosophy. The
new growth to which we should aspire diverges at a certain point from
the old but gains a certain richness from the memories of the latter,
and these memories cease to be painful, in the old sense at least.

FREUD’S PSYCHO-ANALYTIC METHOD 95

It would be worth while to know whether, when you lay
your hand on a man’s shoulder, you are to be taken for a
friend or arrested for assault and battery. The strongest
term which points to the possible practical outcome of your
act is oftentimes the best. A bit of self-indulgence, if it rep-
resented a force which had its rise in infaney, may not be as
harmless as it seems. The child must, at every cross-road, se-
lect and accentuate on the one hand, repress on the other. But
this power of selection and repression, which stands so high
among our attributes, is itself a source of danger. The adop-
tion of this or that principle of accentuation or repression may
become habitual, and some of them are harmful. The child
is like a merchant who cannot oversee all his affairs in detail
and so indicates to his subordinates the general trend of his
policy and then lets them work it out alone. But let him look
out lest he become narrow-visioned and get hoodwinked. The
really wise merchant does not often leave his subordinates to
work out his plans indefinitely by themselves, whereas the
indication of policy made in early childhood is often a de-
cision, in one or another particular, made once for all and for
a lifetime. Truly, the child is the father,—indeed, the mas-
ter,—of the man, to a degree hard to appreciate except for
those who have taken the great amount of pains required for
following the literature of these researches of which I speak
to-night.° Not only is the policy of the lifetime often dictated
onee for all in childhood, but this fact itself is often erased
from memory, that is, it is repressed, and the results of an
early misjudgment are then accepted as if assumed to be gov-
erned by an intelligence cognizant of facts and tendencies
of which in reality it knows nothing.

To summarize once more what I have said: Nervous in-
validism, in the sense in which I now mean that term, is not

*It would be obviously impossible even to indicate here the mis-
chances which often come with the later years of childhood, when
curiosity and fantasy become active; still less those which attend the
oncoming and course of adolescence.

96 HARVEY SOCIETY

only a source of suffering: it is also a sign that those who suf-
fer from it cling—unwittingly but under the pressure of
strong instincts—to modes of thought and feeling which should
be recognized as belonging to childish stages of development.
The mode of action of this tendency is subtle, but a crude illus-
tration of the principle indicated is given in the obvious fact
that depression and feelings of weakness and incapacity,
painful though they are, are often made to serve as self-indul-
gent and childish self-excuses from effort, and as means of ex-
citing self-pity and the attention from others which almost
all children so much erave. The simple recognition of this
tendeney is, however, not competent to banish it from the
mental life of the adult; the whole chain of experiences and
shifting emotions which led to the habit must be laid bare and
scrutinized. It is, then, found that men sometimes allow
themselves even to fall sick, or to suffer pain, or to adopt
some species of asceticism or of morbid self-depreciation, for
the reason that behind these symptoms and tendencies there
lurks often a desire for self-gratification of a childish type
the real roct of which can usually be revealed in detail, and
must be revealed if a radical cure is to be obtained. In
the case of neurotic phobias, it is, essentially, himself, not -the
supposed source of terror, that the patient mainly fears. So,
too, morbid introspection is largely a search for emotional
excitement, the desire for which only disappears when its true
nature is clearly exhibited by the aid of a deep-going introspec-
tion of a totally different, a more wholesome and more rational
sort, through which we see ourselves, no longer as unfortunate
individuals, but as companions in arms in the great march of
social progress; as akin, perhaps, with those whom we had
called sinners, and had pitied at long range, but akin also with
men of devotion and force, whose characteristics we can dis-
cover to have been won by conflicts like our own.

Broadly speaking, it may be said that every man has had,
theoretically, at his birth, the capacity of developing, under
favorable conditions, in such a way that he would have become

FREUD’S PSYCHO-ANALYTIC METHOD 97

possessed of a fairly well-balanced character, and that this
capacity was the best element of his birthright. The condi-
tions required for this development may have been such as it
would have been extremely hard, even impossible, to secure
at the outset, but in the psycho-analytic method we have a
means of readjustment, difficult of application, it is true, but
through the aid of which at least a certain number of those
who have gone seriously astray may be restored to reasonable
health. But for this purpose they must teach themselves to
review their adolescence, their childhood, and their infancy,
and thereby strip off the veils by means of which their ease
and pleasure-seeking instincts had sought to conceal them from
themselves.

The game is worth the candle, for, in my estimation, no
disease from which men suffer causes, in the aggregate, so much
misery as the fears, the obsessions, the compulsions, the need-
less weaknesses, the innumerable faults and vices of character,
by which we see ourselves surrounded. All these ills spring
virtually from three sources,—inherited tendencies, the fail-
ure duly to recognize our spiritual origin and destiny and
the obligations which this recognition should impose on us, and
the absence, during our development, of the conditions neces-
sary for the successful making of the journey from infancy
to adult life.

It is very important to note that the infant starts on his
- journey of life with a series of instincts, motives and inhibi-
tions which are less strongly unified than are those of the adult.
He does not at once feel the intense repression and directive
force of public opinion which is to be reflected later by his
mother and his nurse. Each sensation, each inclination to
seek the renewal of a gratification once felt, he must take at
first, at least relatively, in or for itself and at its face value.
Until the necessity is felt for the subordination of some im-
pulses and the emphasis of others (those which are necessary
for reproduction) as entitled to a relative primacy, the in-
fant’s tendencies might be compared to a set of loose threads

98 HARVEY SOCIETY

of differently colored wersteds, lying side by side or crossing
each other more or less at random, but not yet woven into a
chosen, much less a beautiful pattern. The accomplishment
of this latter task would mean health.

Nervous illnesses and faults of character arise largely as the
primary or secondary results of the failure on the part of the
forees of civilization, brought to bear on this or that individual
child, to set the intricate machinery in action which should
weave his threads into a good pattern. We need not now in-
quire where the fault lies; the main question is as to the ef-
fect. Let it be assumed that some special sort of gratification
is too strong to be lightly abandoned in the child’s mind in
favor of the sort of subordination and co-operation offered by
the oncoming years; or, to make the facts and argument seem
more familiar, let it be assumed that the individual is drawn
by some instinct to remain a child, with a child’s egotism,
longings, whims, propensities, and a child’s world of dreams
and fancies.

I hardly know, though I might guess, how strongly this
audience feels sympathetic to these Freudian doctrines. I do
know, however, how I once felt myself. I well remember my
own first attempt and failure—perhaps fifteen years ago—to
grasp the real thought of Sigmund Freud, then a little-known
physician, now deserving to be ranked as a great leader, and
honored as we honor such men as Charcot, Hughlings Jackson
and Pierre Janet.

I was glancing over a copy of the Newrologisches Central-
blatt at a friend’s house, when my eye was attracted by a bold
claim concerning an asserted common origin for all the psycho-
neuroses. The paragraph stated that these neuroses never
arose except on the (partial) basis of some disturbance of the
sexual life and that the differences in the character of the
symptoms, as, for example, between hysteria and neurasthenia,
were determined largely by the period of life at which this
or that disorder of the sexual life set in. I was impressed
by the boldness and confidence of the statements, but rashly

FREUD’S PSYCHO-ANALYTIC METHOD 99

attributed these qualities to eccentricity and perhaps notoriety-
seeking on the part of the writer, and laid the paper down
with a distinct feeling of disgust: the reasoning, I thought,
could not be correct.

How different are my sentiments at present, now that
through three years’ hard work I have learned what these state-
ments really mean; have made the personal acquaintance of
the author of them and his supporters, and have discovered
what a treasure-house of facts respecting the deep currents of
human life they have amassed. I have come to believe that
if we had the power and the will to turn inward the search-
light of self-knowledge on a large scale, there would be far
less prejudice and cruelty in the world than there is at pres-
ent; far less envy, jealousy and suspicion; far less terror,
disappointment, depression of spirits and suicide; far less
disorders of the nervous system; far less inability to realize
our best destinies. The whole great drama of life is played—
in embryo as one might say—within the mind and heart of
each and every individual, before he sees it played,—for the
first time as he thinks,—on the larger stage of the social world
around him; and this fact is worth our knowing.

To bring about an advance in these directions, an advance
in the prophylactic education of the child, an advance in the
better understanding and treatment of neurotic invalids, would
be well worth all the vast labor expended, or to be expended, on
these investigations. It is not for the purpose of humbling
ourselves that we need to scrutinize our repressed thoughts.
There is little need of final judgments, but much need of free-
ing ourselves through wider knowledge from the unseen chains
that restrain the freedom of the reason and the will,

ILLUMINATING GAS AND THE PUBLIC
HEALTH *

PROF. WILLIAM T. SEDGWICK
Massachusetts Institute of Technology

N the days of William Harvey there was no such thing
as illuminating gas. One of the most striking passages in
the ‘‘ Intellectual Development of Europe,’’ by Dr. John W.
Draper—a New York medical man, who was also a brilliant
historical writer—contrasts unfavorably the unlighted streets
of Harvey’s London with those of Moorish Cordova, which, six
hundred years earlier, were well illuminated: ‘‘ Cordova
[about the tenth century] boasted of more than two hundred
thousand houses and more than a million of inhabitants. After
sunset a man might walk through it in a straight line for ten
miles by the light of the public lamps. Seven hundred years
after this time there was not so much as one public lamp in
London.’’

Illuminating gas derived from the distillation of bitumi-
nous coal was first used in a few private houses and factories
at the end of the eighteenth century and for cities early in the
nineteenth century. A centennial celebration of this latter
event was held in Philadelphia in March, 1912. In the cities
of the United States gas did not become a common illuminant
until about 1850, but by 1855, according to Dr. Samuel Eliot,
the father of President Eliot, there were several hundred
gas companies in successful operation in America. The
revolution wrought by the substitution of gas for oil for
lighting purposes and the reluctance of some to exchange gas
for electricity are pleasantly touched upon by Stevenson in
his well-known sketch in ‘‘ Virginibus Puerisque’’ entitled ‘‘A
Plea for Gas Lamps.”’

* Delivered November 25, 1911.
100

ILLUMINATING GAS AND PUBLIC HEALTH 101

From the beginning until about 1880 there was only one
principal kind of illuminating gas for cities and towns,
namely, that made by distilling bituminous coal and hence
properly called ‘‘ coal-gas.’’ But about 1880 a new kind,
_ known as “‘ water-gas,’’ was invented, which has since, to a
large extent, displaced coal-gas for illuminating purposes.

Water-gas is not made from bituminous but from an-
thracite coal, and not by distillation, but by passing steam
(the vapor of water) upward through retorts filled with glow-
ing coal (carbon). The hot carbon (C) decomposes the water
(H,O) and combines with its oxygen (O), setting free its hydro-
gen. But since there is an excess of carbon in the retort and a
limited supply of oxygen in the water vapor much carbonic
monoxide (CO) and but little carbonie dioxide or carbonie acid
-(CO,) results. The gaseous output of the retort is thus largely
hydrogen and carbonic monoxide, a mixture of gases excellent
for fuel, but burning with a blue flame poor for illuminating
purposes. This ‘‘water’’-gas must therefore be ‘‘enriched’’
with other gases, and for this purpose such gases are added
to it by further treatment of no special interest to sanitarians.
The end result is a gas of fair illuminating and heating qual-
ity, containing a large percentage of the well-known and highly
poisonous carbonic monoxide (CO). At least three times as
much of this deadly poison is usually present in the water-gas
as in the coal-gas sold in Massachusetts, but there is reason to
believe that the water-gas is far more than three times as
dangerous as the coal-gas—very much as a grain of morphine
is far more dangerous than a third of a grain.

As soon as the new water-gas began to be introduced, in
the early 80’s, long-established and prosperous gas companies
in Massachusetts, threatened by the innovation and looking
about for weapons of defence, seized upon and exploited the
fact that water-gas was rich in poisonous gases and hence dan-
gerous to the public health; and from that time forward, for
this and other reasons, the illuminating gas question has be-
come a public health question.

102 HARVEY SOCIETY

In 1885 an article bearing the same title as the present
paper appeared in the Annual Report of the State Board of
Health, Lunacy, and Charity of Massachusetts. It was care-
fully prepared by the able Secretary of the Board, the late
Dr. Samuel W. Abbott, and the reason for its appearance
at that time was the recent perfection of a simple and con-
venient patented process for the manufacture of the new
kind of illuminating gas, then and since known as ‘“‘water’’-
gas. This was placing upon the market an illuminating
gas easier and often somewhat cheaper to make, and ranking
higher in candle power, than the ordinary coal-gas derived by
the distillation of bituminous coal, but a gas also much more
heavily charged with carbonic oxide (CO). Promoters of the
new process naturally urged its adoption upon the old and
established gas companies, which in some cases began to make
use of it, especially for supplementary supplies, but in other
cases, particularly if they were already prosperous, refused
to have anything to do with it. Advantage was also taken
of the water-gas process to form new and competing com-
panies, charters being sought on the promise of lower prices
and higher candle power for gas. Attempts were likewise
made to buy out at low prices long-established and prosperous
companies occupying inviting territory, by threats of invasion
and competition with gas of lower price and higher candle
power.

In Massachusetts, a comparatively thickly settled and there-
fore attractive territory for the manufacture and sale of gas,
there were in the early 80’s many and prosperous gas com-
panies, and these for the most part, under the leadership of
the largest—the Boston Gas Company—refused to adopt the
new process or to be frightened by threats of competition into
selling out at low prices. But when the water-gas interests
undertook to obtain charters in Massachusetts for new and
competing companies, they encountered a formidable obstacle
in a statute (enacted in 1880) forbidding the distribution and
sale of illuminating gas containing 10 per cent. or more of

ILLUMINATING GAS AND PUBLIC HEALTH 103

CO. This law it was therefore necessary to have annulled
before the new process could be introduced into that State.

A battle royal for the repeal of the law now began be-
tween the older coal-gas companies on the one side, who did not
eare to pay for or use the new process, or did not desire
to sell out to the new companies, or did not want competition,
and those newer companies which for one reason or another
wished to enter Massachusetts territory and sell and distribute
water-gas containing more than 10 and often as much as 30
per cent. of carbonic oxide. Popular attention was drawn
by the old gas companies to the sanitary aspects of the ques-
tion, and the battle before long raged fiercely around the ques-
tion of the public health. Meantime the State Board of Health,
Lunacy, and Charity referred the mooted question of the rela-
tive poisonous properties of the two gases, coal-gas and water-
gas, for investigation to two professors of the Massachusetts
Institute of Technology—one, the eminent sanitary chemist,.
the late William Ripley Nichols, and the other, then a physiolo-
gist, the present author. These investigators soon after made
a report, based upon extensive experiments upon animals,
showing, as might have been expected, that much greater dan-
ger exists in water-gas than in the ordinary coal-gas (Report
of Massachusetts State Board of Health, Lunacy, and Charity,
for 1885, p. 275). In the same report Dr. S. W. Abbott, then
Secretary of the Board and an excellent statistician, published
the paper already referred to above, in which he showed that
for the preceding 20 years there had been but four deaths
from gas poisoning in Massachusetts and predicted many more
if the 10 per cent. limit should be abandoned.

Victory in the Legislature rested for a time with the older
companies. But in 1888 the Gas Commissioners (who had been
created in 1885) were empowered to license certain companies
to make and sell water-gas for illuminating purposes; and in
1890 the 10 per cent. statute was repealed, because meantime
the opposition of the older companies was for one reason or
another relaxed, while the State Board of Health (as it was

104 HARVEY SOCIETY

now and had since 1886 been called) made no effective ob-
jection. Commercial conditions had changed, and many of the
coal-gas companies now wanted the privilege of making water-
gas if it suited their convenience. Moreover, water-gas was
being widely used in other States without public protest, and
when the commissioners recommended the change it was
speedily made by the Legislature—with what obviously dis-
astrous consequences to the public health we shall learn in the
present paper. Of the unobserved and perhaps imperceptible
consequences, such as diminution of vital resistance and in-
creased susceptibility to disease either constitutional or in-
fectious, we have, and in the nature of the case can have, no
exact knowledge. There is reason to believe, however, that
here also the consequences, if less disastrous, have been no less
real.

MORTALITY FROM ILLUMINATING GAS POISONING IN MASSACHU-
SETTS: MORE THAN 1200 DEATHS IN THE LAST 20 YEARS

It was predicted by the investigators employed by the State
Board in 1884 and reaffirmed by Dr. Abbott in 1885, that if
water-gas should replace coal-gas in Massachusetts the conse-
quences to the public health would probably be dangerous if
not disastrous. Other experts of equal or greater eminence
took precisely the opposite ground and even ridiculed the
possibility of any such consequences. Among these were Pro-
fessor C. F. Chandler, of Columbia University, and the dis-
tinguished English chemist, Dr. E. Frankland, who stated in
a letter read during these hearings: ‘‘ I have no hesitation
in saying that it (water-gas) may be used with safety both
in public buildings and private houses. I should be delighted
to substitute this pure and powerful illuminating agent for
the gas with which my house in London is at present supplied,
although it is used in all the bedrooms.”’

More than a quarter of a century has since gone by and
there are now available for study the results of a considerable,
though by no means total, replacement of coal-gas by water-

ILLUMINATING GAS AND PUBLIC HEALTH 105

gas during a period of about 20 years (1890-1909). The
author of the present paper and one of his associates, Mr.
Franz Schneider, Jr., have accordingly undertaken a careful
inquiry to see how far the predictions referred to have come
true. The problem is of course complicated by the fact that
in spite of the legislative permission to manufacture and dis-
tribute water-gas, this has by no means wholly displaced
coal-gas. The results at hand, originally published in the
Journal of Infectious Diseases, vol. ix, No. 3, 1911, are there-
fore not such as we might have obtained if the replacement had
been complete. Since 1890 some companies have made only
water-gas; others, only coal-gas; many have made a mixture
of the two, and some have made each intermittently. Still,
the broad fact remains that an increasingly larger amount of
the poisonous gas, CO, has been distributed since 1890 than
before that date and not only absolutely but relatively to the
population. The matter is further complicated by the use of
illuminating gas for suicide, a subject which requires, and
in the present paper will receive, special consideration and
discussion.

One good result of the long and active agitation in Massa-
chusetts was that a State Gas Commission had been provided
for in 1885. Another was that in 1888 the Gas Commissioners
were required to investigate, keep a record of, and report all
deaths (or injuries to health) from gas poisoning within the
State. From 1888 onward, therefore, we have for Massa-
chusetts a fairly complete report of fatalities and other con-
sequences of gas poisoning, and one probably far better than
any possessed by any other State. It is perhaps the only
record of the kind existing anywhere. Fortunately we have
also, for the same period, the returns of the Medical Examiners
concerning deaths from illuminating gas—a body of experts
whose opinions possess expert value.

We have taken for study the fatalities, only, from gas
poisoning. Of the numerous injuries which do not result
fatally we have, and can have, no complete record. Some are

106 HARVEY SOCIETY

reported by the Gas Commissioners, but many are
never reported at all and many less striking and seemingly
transient effects, such as headache or malaise, are neither heard
nor even thought of as due to gas poisoning.

As stated above, we have obtained the records of death
from gas poisoning in Massachusetts from two sources, namely,

TABLE A.
DeEatTHS FROM ILLUMINATING GAs POISONING IN MASSACHUSETTS.
(1886-1909.)
Years Ending Dee. 31. Eee Pia Retaeag:

SES yey ae eee tes pete asus, Le SMs became. Noy iy iu 5 0
LTE Ce x AAP oUF gern ERENCE Atak 6 9
ES SS eee eee Manta? ce SEAL STN AO Go ce) Dy 6 0
Th STOAU NES ops (2 cuenta een RENN Pe ME SAR a Me OM Ma A 5 2
SOO ae ee ce ert en Piece rence eee ee eres 12 10
BS I ei: SYS RIAy Sey AAR Oe REL CE IS 2 WP a Di tees ane 16 14
TSO PAA ARGU hs SOT oF REIL SY SURED yO SG Bh 28 18
1 foto BS Bence Bh cl Ais ACH emer tine tals hummel Abie 27 25
1 ofO Ye Dae eats CNTY APPR ies DHT e a a anes Cas Boat MBS 43 33
POO Sie neiere ples eae ee Tea doy ae hae bola NN a 31 26
Tey ea ede pee eelat toate hah A eli tbs SV ale otad 2 Retake 52 51
1 eo eae ANS Mh ae plan a Ah eA Cd ey Ae 63 58
MBO Sk eos em ale det ee mea eno cod abt h a Ca 78 be
1 oko) Oi STs oe rite ited 1 Ri hy itd or las Se 65 65
GOO ire ee PEAS AV ares Rie Fh Sy Se Sas 45 46
1 RTD Resta Oe TE MITA Day ESN PN ate Su aE 37 37
TOA thar ins epee A a dee nee in Annet, BiB RS gad a 63 62
OOS ee eaee te rela Oe ete ers eee 71 (P:
5 S(O ES OR ANE I RIAL OS ARENA Caled Je enya 61 59
HAC8 OSS et Rik aie aa we ica Bd Pe EEG a al mk ERO 77 72
TOO Gi Bees eee br ee ee sy ea eae 68 71
TOO Fess ha Fee a cacteus clothes cierto ee 147 145
ge SPER Sd ALE UE AA Ra PURI SPAS ot kbd 123 115
EGO OI a TER Ree OI i ln ei deh 102 99

POGUES SPs Masia eae ee wees 1,231 1,157

the reports of the Gas Commissioners, and the returns of the
Medical Examiners. The former are published in the Com-
missioners’ Annual Reports, the latter in the State Registration
Reports. The Gas Commissioners’ records we owe to a pro-
vision of the law already referred to, permitting the use of
water-gas, but at the same time requiring all gas companies to

ILLUMINATING GAS AND PUBLIC HEALTH 107

return to the Commissioners a written report of any death or
injury due to gas distributed by the company in question. On
the whole this arrangement has worked out fairly well, al-
though in the early years the Commissioners complained with
reason that some deaths were not reported. The Commis-
sioners’ records begin with the year 1886 and it is interesting
to note that poisoning by illuminating gas did not earn itself

Cuart [.

Seen a Ea
| lscduef eter} | dosdei| | rebishel | [DE
ee
See D

CO aN J Metsret |
\ ea ae
selene lead

a separate place in the classification of deaths reported by the
Medical Examiners until that same year. The figures of the
latter are also available, therefore, since 1886. For data pre-
vious to 1886 we have only Dr. Abbott’s valuable paper of
1885.

The table now given (Table A) shows side by side the fig-
ures derived from the two independent sources mentioned.

108 HARVEY SOCIETY

These data are for the calendar year indicated, and include
only deaths from poisoning by illuminating coal-gas and water-
gas. Deaths from oil gas or acetylene gas and deaths caused
by gas explosions, or from burning by gas, have been excluded.

The table shows substantial agreement in the two sets of
data, especially in the later years. The Medical Examiners’
figures are probably the more accurate.

Some of the salient features of this table are the sharp rise
beginning in 1890 from a very low previous level and con-
tinuing to a high maximum in 1898, with a fall to a lower
level in 1901, followed by a rebound which in 1907 reached
the highest point in the entire table. From five or six deaths
each year before 1890, the number rose to 147 deaths from
poisoning by illuminating gas in 1907. Previous to 1885, ac-
cording to Dr. Abbott, there had been only four deaths dur-
ing 20 years.

The same fluctuations which appear in this table may be
seen in more graphic form, but as death rates, in the lowest
curve—the heavy black line marked ‘‘ Gas Poisoning, Mass.’’—
on Chart I.

Variations corresponding more closely to those in Table A
may also be seen upon Chart II in the heavy black line marked
‘‘ Deaths by Gas Poisoning.’’ It should be noted, however,
that the correspondence of these data is not exact in all cases,
since the figures in the table above and the curve on Chart I
represent calendar years and rates, while the heavy black line
on Chart IT represents actual deaths and years ending June 30.
The highest point of the line on Chart II thus falls in 1908
and not as on Table A and Chart I, in 1907.

SOME DEATH RATES FROM SCARLET FEVER, FROM MEASLES AND
FROM ILLUMINATING GAS IN MASSACHUSETTS
AND IN RHODE ISLAND

We can best realize the growing importance of illuminating
gas as a cause of death by comparing its mortality rate for
a period of years with the death rates from such familiar dis-

ILLUMINATING GAS AND PUBLIC HEALTH 109

eases as scarlet fever and measles in States having trustworthy
vital statistics. For this purpose we have computed the fol-
lowing statistics for two such States, namely, Massachusetts
and Rhode Island:

TABLE 1.

DeatH RATES FROM SCARLET FEVER, FROM MEASLES AND FROM ILLUMI-
NATING GAs IN MASSACHUSETTS AND IN RHODE ISLAND.

(Per 100,000.)
Illuminating | Illuminati
Calendar Years. Pea Olas) oo | “Gey

LES ie oe ere 28.80 22.08 | 0.29
LS OE ee Zone 10.33 0.29
ISS Se Ne 8.49 7.85 0.23
fee os Se 8.76 5.09 0.54
Lilo -e ee 10.74 LOLS 0.70
WLS 28 .56 S78 1.19
Doh Sin. + oe eae 33.80 2 eS
MOA eee ose base 26.51 4.00 1.76
OE Einar rn 19.31 4.63 1.24
LEM AL a 9.73 5.35 2.03
Uo Tie 13.05 6.03 2.40
ESO SMT PLS ss a'si5-s! g 5.25 2.05 2.91
LON AL led er 8.56 8.78 AER Y/
LOTS J ee 13.94 LG RE7 (Ff 1.60 1.63
LST Lue See 13252 6.03 ico 3.42
DLs 2 a 10.84 11.53 2.18 4.01
Ll 2) 6 17.42 8.44 2.43 6.10
LT. os ee 4.65 5.39 2.06 4.69
ieee 3.90 5.89 2.56 1.92
Ly | hve ae ee 4.39 6.76 APA 7.50
LSU 2 i re 9.04 5.18 4.67 eas
TES Ws ee eR 11.46 10.27 3.82 L415
eae ee, Se 7.86 4.77 3.10

Table 1 shows strikingly how important poisoning by illu-
minating gas has recently become as a cause of death in Massa-
chusetts and in Rhode Island; and the same facts are dis-
played graphically by the diagrams on Chart I (p. 107). The
death rate from the two contagious diseases (scarlet fever and
measles) has evidently greatly declined, while that from illu-

HARVEY SOCIETY
The death rate from poisoning by illuminating gas was

minating gas poisoning has greatly increased, so much so that
higher in Massachusetts in 1907 than from scarlet fever in

the latter bids fair soon to exceed the former.
1905 and 1906, while in Rhode Island the death rate from

illuminating gas from 1903 to 1907 was at times higher than

110

a Sa 2 aS a ee eS ee
RRR ee ese eee eRe eeea ees eese
Ete Skst: Bees neias Bee Seneaeee
ShaBeS Se eae Reet eeSeerekhees
EAS sE 2aeMeeaee ee Ses sessear
(222 sce ae aes eae ae Vee Sa
JGGebe = he es seas oe aa ae See
Sk SS eenhse te aS hs Ree eo eet
Bis se ees ese oe olan eee
gt eget
Ps a a a 9 at a
SRR ESS eae kkia===SS SS Seah ar
£12 eee Nee ee
eC ee

Cart II.

SaPEPHRE EEE EEE pape
: SCARE ECACC PS Roe

pp
2

Poisoning by illuminating gas has evidently become in Massa-

chusetts and in Rhode Island a cause of death nearly as ef-
fective as is scarlet fever or measles. It has of late years claimed

that in Massachusetts from either scarlet fever or measles.
as many victims as has typhoid fever in some American and

many German cities.

ILLUMINATING GAS AND PUBLIC HEALTH 111

AMOUNTS AND KINDS OF ILLUMINATING GAS MANUFACTURED IN
MASSACHUSETTS (1886-1909)

The following table (Table 2), the main features of which
appear also on Chart II, p. 110, shows the amounts of total il-
luminating gas (coal-gas and water-gas) and of water-gas
manufactured in each year in Massachusetts. The data are de-
rived from the Annual Reports of the Gas Commissioners.

TABLE 2.

Amounts oF ILLUMINATING Gas MaprE AND OF WATER-GAS, AND DEATHS
FROM ILLUMINATING Gas IN MASSACHUSETTS.

(1886-1909.)

Total Coal- and
; ¥ Water-Gas Made Deaths from
Years Ending June 30. ae Ge Mees (Million Cu. Ft.) | Illuminating Gas.

ls oS pele Aer 2,625 12

a ne 2765 28 5
a ae 3,010 47 8
ve ae 3,156 78 4
are 3,346 212 7
er. 3,300 777 19
0 ae 3,370 1,231 21
a 3,594 1,467 26
ee ee 3.671 2,022 29
i. ces a 3,955 2,413 45
2 a ea 4,639 2,876 33
ee 4,731 3,090 63
Be es secs. 4,901 3,167 77
NP eee in. 5,120 3,265 70
ee 5,608 2,881 50
ea Sian 6,059 1,961 37
<p A ea ee 6,372 2,400 48
ea 7,776 2,989 78
ES i 7,882 3,335 64
SL lt a arr 8126 3,373 64
TE a es 8,902 3,536 74
Me a te Co 9,998 4,471 92
Pe re says 10,902 4,862 148
Pe Pot, bytes a 11,360 5,518 114

The same facts are depicted graphically upon Chart II,
which deserves and will repay careful study. The apparent
discrepancy between these data of deaths and those given on
other tables is due to the fact that the ‘‘ years ’’ end here on
June 30, and not as in the other cases on December 31.

112 HARVEY SOCIETY

A COMPARISON OF MORTALITY FROM ILLUMINATING GAS IN MASSA-
CHUSETTS WITH AMOUNTS AND KINDS OF GAS MANUFACTURED

From Table 2 and Chart II it appears that the total quan-
tity of illuminating gas made in Massachusetts has, on the
whole, increased rather steadily, year by year, since 1886.
Once only has there been a slight decrease (in 1891) and at
times (as in 1896, 1903, 1906, 1907, and 1908) the increase
has been very rapid. The curve on Chart II shows also on the
whole a much more rapid annual increase of output in the
later than in the earlier years.

The total quantity of water-gas made shows likewise, on
the whole, a great increase since its distribution for illuminat-
ing purposes became legally possible in 1890. But the water-
gas curve, though approximately parallel to the total gas curve
for the years since 1901, was not so before that time. On
the contrary, from 1890 to 1896 it was rising much more
rapidly; from 1899 it was nearly parallel; and from 1899 to
1901 it declined sharply, whereas the total gas production in-
creased more rapidly than before.

The third line on Chart II, the heavy black line, shows the
deaths, year by year, from illuminating gas in Massachusetts,
and, like the other two lines, it shows on the whole a great
increase since 1890. It is, however, much less regular in form,
and the increase which it shows is much greater than that
shown by the other two lines. ‘To the line of total gas produc-
tion it shows only the most general relation of rapid increase,
and that only with numerous and striking exceptions of de-
parture, as in 1896, 1899, 1900, 1901, 1904, 1905, and 1909.
If the number of deaths had merely increased pari passu with
the total amount of gas manufactured, we must have supposed
that the poisonous quality of the gas had remained constant
and the habits of the consumers unchanged. But this is clearly
not the ease. The deaths increased very much more rapidly
from 1890 to 1898 and from 1901 to 1908 than did the total
amount of gas made, while from 1898 to 1901 and from 1903
to 1906 deaths actually decreased while total gas production

ILLUMINATING GAS AND PUBLIC HEALTH 113

increased. We are therefore driven to seek some other explana-
tion for the great increase of deaths from illuminating gas
than the mere expansion of the industry and the increasing
use of gas.

For an explanation we need not look far. If, instead of
comparing the death curve with the curve of total illuminat-
ing gas, we compare it with that of water-gas made, we find
a remarkable, though not a perfect, general correspondence.
Except in 1896, 1899, 1904, and 1909, this general correspon-
dence is close and striking, both curves rising and falling to-
gether, though often at different rates. The general increase
in deaths, barring the exceptional years noted, may therefore
be readily explained by the general increase in the amount of
water-gas made.

From 1898 to 1908 the amount of total gas made had
doubled, while the fatalities had not quite done likewise. But
while the quantity of total gas made increased about fivefold
from 1886 to 1908, the fatalities increased nearly thirty fold.
At the same time we find the variations in the amount of water-
gas manufactured coinciding much more nearly with the fluc-
tuations in the number of deaths. The remarkable increase
of such deaths in 1891 corresponds with the first appearance
of any large amount of water-gas. And when the deaths
reached a maximum in 1897-99 water-gas had reached a per-
centage proportion of the total output which it has never
equaled either before or since.

In 1900 the New England Gas and Coke Company installed
a large coal-gas plant in Everett, and the effect of the intro-
duction of their product into the illuminating gas of the Metro-
politan District was to produce an actual decrease for three
or four years in the total amount of water-gas manufactured
in the State. It is noteworthy and significant that this de-
crease corresponds closely with the low phase of 1901 in the
curve of deaths by gas poisoning. But, as indicated by the
diagram, the natural growth of the gas industry soon called
for more gas. The check to the production of water-gas in

114 HARVEY SOCIETY

1901 was only temporary, and the increased output since 1901
has been attended by a corresponding increase in deaths from
gas poisoning.

In consideration of all these facts we are warranted in
concluding that the amount of water-gas produced stands in
some close relation to the number of deaths by illuminating

TABLE 3.
PERCENTAGE WuicH WaTER-Gas Mapre was oF TotTau ILLUMINATING
Gas Mapg, AND DraTHS PER BiLtLIoN Cusic Freer or TotTau
ILLUMINATING GAs MapE (MAssaAcuuseEtTts, 1887-1909).

Percentage of Deaths per Billion
Years Ending June 30. Water-Gas Made Cubic Feet of
to Total Gas Made] Total Gas Made

SS Cane ate ietesits lene tie eieteleiernte ele Siavelaions ee 1.01 1.09
DSBS! Mittal a eters saree ott io: heres ede erate eed cere 1.56 17
BRB O SS ao, Resta Pas ie wre aie sich is jo eines Siete 2.43 0.64
MOON, Papicveristere tice avonhris: aie cpterantabevepeterste 6.34 2.10
DOU ey ec Ata hale sto sheyern chee ae Sate ieee ete 22.20 5.76
Dee Apes e wigtcya clei icietein « oouaeneuahs eiecs a= 36.60 6.24
MESO eSoys chee cfore oesittcte ie (aro) nya ates ape eset a te 40.80 7.24
PROMS ie OL7..8 ley cakaia abies enimrenaentermenets eft 55.00 7.90
DD ee eo sects caplet eiametctes cal chemateteein ae 61.00 11.39
FUE Bea Ee GER SEIE tT fran curg Gey NE tr CIC 1 62.00 7.12
BRO aye eons cit pene aaseoeateberers 6 0 eters et 65.40 13.31
DOORS Sh ictics on siete steere iepmerae eaters 64.60 15.70
FSO a eek cy ete exe eqeithnuetreeaye ai evenale eayele 63.80 13.67
NOOO Fe Sek: tin eve Bia eos esate sia eran 51.40 8.92
OIL loves cp eslapnint ops meeyens (a ean elegans aes ae 32.30 6.11
BOOZ e Sea istrists cherie a ste ous estonia sl ahekeieey sticks 37.70 7.54
POS is ce Sheet aha cl cietceteieiale & athens alsin acme 38.40 9.78
TOU AAR eerie acl s Aetehets fe. hans 42.30 8.12
LOO s) ais o teleost he sree veep ee rele sean fa 41.30 7.88
VOOG 4 scha) ie Satie isch iaeints heyeeee taba s aie 39.70 8.31
TOOT.) § Sethe n as stars Cate abies ape ete ar aah ates 44.70 9.20
NGO. ska scthreraaate trees Gane taNG che ocote starele crac 44.50 13.57
T9O9. Bc co. oes aemanes eye a ete Saree ene 48 .60 10.05

gas. This conclusion is justified and confirmed by a com-
parison of the percentage which water-gas formed of the
total gas manufactured, with the deaths per billion feet of
total gas produced. If the water-gas is really to blame, the
larger the percentage of water-gas the more dangerous should
be each unit of the resultant product. On the other hand,

ILLUMINATING GAS AND PUBLIC HEALTH 115

by dividing the deaths from gas poisoning by the total amount
of gas made, we should obtain a measure of the poisonous ef-
fect of a unit of the total gas. In other words, if the theory
that water-gas has been the primary cause of the deaths by
gas poisoning is true, we should expect to find some general
agreement between the percentage of water-gas to total gas
made, and deaths by gas poisoning for each unit, such as a
Cuart III.

Seo pad: nee eene
| -F [PERCENTAGE| O} IAS MADE. + |
TES peis by cks a aT ree of DTAL GAS. [=| |
eee eer aera joop PoPyLapiony | | oT |
PT ty | TT dMAssas ao? ttt

PTT TTT Tey yy iNy et tt Nseag/ Tx
eH

billion feet, of total gas made. That such agreement actually
exists appears from Table 3 and its corresponding chart
(Chart III).

Table 3, and especially Chart IIT, shows a remarkable con-
cordance between the percentage of water-gas manufactured
year by year and the corresponding death rate (ratio) from
illuminating gas per billion feet of total gas made. In spite

116 HARVEY SOCIETY

of some differences (as, for example, 1896, 1904, 1906, 1908,
1909), it is difficult to avoid the conclusion that the water-gas
curve and the death curve stand in the relation of cause and
effect.

The agreement between the variations in the percentage of
water-gas made and the number of deaths year by year is ob-
viously not absolute, but when we reflect upon the actual con-
ditions under which water-gas is made and distributed, we
may well be surprised that the agreement is as close as it is.
For illuminating gas is sold in Massachusetts by many com-
panies and under a great variety of conditions. Some com-
panies distribute only coal-gas and some only water-gas, but
most distribute a mixture of the two. And this mixture may
vary widely from time to time in the percentage of the two
gases. Again, there is, as we shall learn below, a marked
seasonal variation in the deaths from illuminating gas, and
there is good reason to believe that the mildness or severity of
Massachusetts winters may cause annual as well as seasonal
variations in the mortality from gas poisoning. These various
factors naturally forbid any absolute correspondence between
the amount of water-gas made and the deaths from gas poison-
ing. When we consider this great variety of circumstances,
the wonder is, not that the two curves occasionally differ, but
that they run so nearly parallel.

THE USE OF ILLUMINATING GAS IN MASSACHUSETTS FOR PURPOSES
OF SUICIDE

Since 1890 illuminating gas has been gradually discovered
by the public to be a convenient and effective means of suicide.
Whereas before that time it was very difficult to commit suicide
by the use of illuminating gas, and probably very few would-
be suicides resorted to its use, it has come of late years to be
one of the easiest and surest agents of self-destruction. The
reports of the Medical Examiners contain ample evidence of
this fact.

Table B, prepared by us from the returns of the Medical

ILLUMINATING GAS AND PUBLIC HEALTH 117

Examiners, shows not only the use, but the increasing use, of
illuminating gas for purposes of suicide. At the same time
this table is a sufficient answer to those who have the assur-

TABLE B.

DeatTus FRoM ILLUMINATING Gas Porsontne (MASSACHUSETTS, 1886-1909).
(Medical Examiners’ Returns.)

Years Ending June 30 Accidental Deaths} Suicidal Deaths Total Deaths

Nha cet fal hs ond asa oi i 1 2
SS (ae cactacls a's sie eaves 8s 4 1 5
SSB erct eels elec sels cate x 7 1 8
US Oates tates io. ifs ae8 2 2 4
SOO aevsieveraciste se s 2st 5 2 U
BSR syencces as se wiansress 18 1 19
SO ele sect cia Site, oWis.+ sce. & aces 9 12 21
SO eye rey Sas vie ce edie oe Gi 9 26
MG Aeerere rere sis eo siete sige 14 15 29
ih), S48 Ge ae eee 28 17 45
LRSSOSS: 45 Gg I ae eee ea 206 13 33
USO 6 ee ae ee 47 16 63
SO Seria hy ay oleters cisions oe 48 29 ie
LU) es Be ee 35 35 70
Ll at ER a 35 15 50
PUNO espe te eattehy oie ks eyaye.o jie: aro ve 11 26 37
GLU Pe eS tO ee 9 39 48
MO tceetciiol S40 o(ateraie) eevee: 47 30 77
OA aera beass) haber o:skavaia/d-a 29 35 64
MOO Weare ce ss vee. dinns esate oles 41 23 64
oo Le ener 35 39 74
LOE cose GANG) Caer ORIOL ERR IPR 41 51 92
eS os: 5, ae, acc 64 55 93 148
OOO Pet tev al sieveisyers,c ssular aie 43 71 114
MN di 2 es ik aha cret wyate a 23 3l 54
OTA, aks I a Sa 624 607 1,231
* First six months. {Second six months.

ance to proclaim that, excepting as it is used by suicides, water-
gas is no more dangerous to life than is coal-gas.

Of the 1231 deaths by gas poisoning reported by the Medi-
eal examiners in the years 1886-1909, 607, or 49.4 per cent.,
were reported by them to be suicides and the remainder acci-

118 HARVEY SOCIETY

dental deaths. Table B gives these data in detail for the
separate years.

We have also computed, for the same period, the death rates
from illuminating gas and those by illuminating gas from acci-
dental sources and from suicidal sources, as reported by the

TABLE 4.
Derata Rates FROM Porsonina By ILLUMINATING GAS AND FROM ACCI-

DENTAL AND FROM SUICIDAL POISONING BY ILLUMINATING Gas
(MassacHusetts, 1887-1909).

(Medical Examiners’ Returns.)

Years Ending June 30 Gris Gas Accidents Gas Suicides
PSS eee teers Baas tee 0.251 0.19 0.5
PSSST Ue sre tee S Mrice ee 0.381 0.33 0.05
PESO rckaretiolunsiet ok, deetetcres 0.180 0.09 0.09
TOO ee Matera ait sete etek 0.31 0.22 0.09
TSO tend ee rei c sks vee 0.831 0.79 0.04
DOD error eee ore. 0.690 0.33 0.51
TieLU RS ea RS, etek Seen i 1.034 0.71 0.38
1 a} 97: 9) he ATS AR BEES et A Bue ae 1.184 0.57 0.61
SOS eek sl eae ace 1.804 12 0.68
PROG rete: benno: 1.129 0.78 0.51
LOT eens ce cketin: Ped cen yaks 2.40 1.79 1.61
SOS faecal aoc, Bye creer 2.87 1.79 1.08
1 eo ee ee SERRE sary i Pata}5) 1.82 127
1900 Sarat. pee pee coe 1.78 1.25 0.54
DODDS eo ARES erate 1.30 0.39 0.91
Ae] OE, A Ae ohrnoroen stad be 1.66 0.31 1.35
WGOS Bra citer. eater 2.63 1.61 1.03
TODA tytn. ae iene ee 2.16 0.98 aes
LO Qe yer Uicts toenail te 2.13 1.36 0.77
PGOG Feicccte eke earn 2.41 1.14 Loe
EGO FALE et eee eee eee 2.92 1.30 1.62
T1908 Sh rt tok es eet 4.60 ibaa 2.89
1 UU Ge Aap nte Aisi Laaatoe 3.46 eed | 2.16

Medical Examiners (Table 4 and Chart 4). It is hardly nec-
essary to repeat that these, while obviously open to the ob-
jection that they represent merely the opinion of the Medical
Examiners, are the best data we have and are probably on the
whole not far wrong.

ILLUMINATING GAS AND PUBLIC HEALTH 119

It may, of course, be urged that it is often difficult even for
expert medical examiners to discover whether or not a particu-
lar death was suicidal or accidental. But even if this be
granted and if some deaths reported as accidents were really
suicides, the reverse may likewise be true, and there is no good
reason to doubt that in a large percentage of cases the Medical

Cuart IV.

| | DEATH RATES st chegicaLexabiners reruns) | | | | | | | |
| | [FROM ILUUMINATING|GASPOISONING| | | | { | [ | 1 |
| | |FROM BuicipDes|By GAS] | | ti tT | TTA TT TT
| | [FROM ACCIDENTS BY|GAS.] | | | {| TIAL TT TT
| | lemagsacnbortts, lies7qiopo> | | | | | | | AL TT TT
__ J TNE eR RRS RANA
_ SSR RRR RRR eee
EET GHGnEGRGnann
| (SRR RRREEP SRR ERRARS SUees
LAAN AL iE
_. _S DERE SE sei Ge heehee
meee ea Nee eee |
_ SERRE RaSh Te eee Ae
_ 4 SQRC UREN ENY eee PE Nae
PT Tt Tt TT VIET TY TW AAT AI ZY | Nash ort _|
CEU RERD2ZP VAR Awe A EEL
PECTIN SNe ACEC
Beye

eee

Examiners’ returns are correct. If any reasonable doubt could
exist as to the fact that many accidental deaths do oceur from
poisoning by illuminating gas it would be dissipated by an
examination of the data shown on the following table (Table
5) and its corresponding chart (Chart V), on pp. 120-121.
This table and its corresponding plate show how sudden
was the increase in 1891 of deaths from illuminating gas, an
increase much more reasonably explained by increase in acci-
dents than by increase in suicidal use of the new and as yet

120 - HARVEY SOCIETY

generally unknown poison, especially when we observe that

this increase was accompanied by a decrease in the whole num-

ber of suicides for the year. Again, in 1895, with no increase

in the whole number of suicides, there was a very large in-

crease in the number of deaths from poisoning by illuminating
TABLE 5.

DEATHS FROM SUICIDE BY ALL Mertuops, DEATHS FROM ILLUMINATING
Gas, AND PopuLATION (MASSACHUSETTS, 1887-1909).

(Medical Examiners’ Returns.)

: 7 ne 7
Years Ending Junsgo | Suigiteeby All | Desthe tom || Mamuaieaaes

PSS 7iecearnacihorae aren 152 5

SSS Otel n ne cite oe adres yea 8

1 ooh) Eis euch ert Meh Otel eae 196 4

TSO evs matrens ie oaks emieus Tora 202 7 2,238,943
TST Seis s actin 194 19

SOD eae er ecanae heres 2 231 21

Ufo U By ue) Cree ate acne MER IEEE 270 26

DS area tcacin staph statthones 284 29

PSO Deas ete a cigaae 282 45 2,500,183
SOG Siac lsasnteyeteo eee 269 33

ESO ehyenenestete win eretake 304 63

US OS eters chee: Geaeiocte oh ie 321 Ga

ASO OE on sroyais ists eerie eons 323 70

DOQQ Ea ceo ntarerna siento 312 50 2,805,343
OOM oe Acr overs oie re hers 347 37

OOS aia ceds eh ila ghcieretecte 350 48

VOUS aie Je erat cele sastas) as eereae 358 aire

NOOSE. Houten ek One 369 64

UGOS weeks eh cine SOK 366 64 3,003,680
SOG. cys leet macro 338 74

ISO. Shen cok oe oe 390 92

OOS tales cts ahaha 494 148

LOO GS a ike Broce coor teteiats 476 114

gas; in 1904, while the whole number of suicides was increas-
ing, deaths from illuminating gas decreased; while in 1906 the
reverse was the case. Undoubtedly, there is on the whole
a striking correspondence in the forms of the two curves, such
as ought to exist when we remember that (as shown in Table
B) about one-half of all the deaths in the lower line are an
important factor in the upper.

ILLUMINATING GAS AND PUBLIC HEALTH 121

A STUDY OF THE SEASONAL DISTRIBUTION OF DEATHS FROM
ILLUMINATING GAS IN MASSACHUSETTS
We had not been studying the general subject of illuminat-
ing gas poisoning very long before it became plain that such
poisoning bears a close relation to the seasons. And this re-

CHART V.

DEATHS FROM GAS Poisoning, DEATHS FROM SUICIDE BY ALL
METHODS, AND POPULATION. MASSACHUSETTS 1887-!907

“ABse ae,
ABSC-” YEARS Enbing June 30. FW a i
ee sa ee Se
Suiciwwes 20 40 60 60
ee Ao

Sor LinE - DEATHS BY GAS POISONING.
DASH LINE -SviciDES BY ALL METHODS.
Dot % DASH LINE ~ POPULATION,

1887 88 89 1890 9) 92 93 94 95 96 97 98 99 1900 01 OAR O35 OF O5 O

lation proved to be almost precisely what might have been an-
ticipated. Deaths from illuminating gas are comparatively
few in summer and comparatively many in winter, as is shown

122 HARVEY SOCIETY

by the first column in the following table, and by the heavy
black line on the corresponding chart (Chart VI) based upon
it. The reason is, of course, because in summer, with open
windows, short nights, and outdoor life, people in Massachu-
setts are much less exposed to gas poisoning than in winter,
when they are housed most of the time, often in apartments
piped for gas and having little or no ventilation. Similar
considerations probably make gas poisoning also largely a mat-
ter of latitude—northern cities suffering more from gas poison-

TABLE 6.

SEASONAL DiIsTRIBUTION OF DEATHS FROM ILLUMINATING Gas, OF DEATHS
By ACCIDENT FROM ILLUMINATING Gas, OF DEATHS BY SUICIDE FROM
ILLUMINATING GAS, AND OF SuricipEs By ALL METHODS
(Massacuusetts, 1886-1909).

(Medical Examiners’ Returns.)

Total Deaths |} Accidental Deaths} Suicidal Deaths Suicides by All

Month r rom
"i lheninative Gas illuminating Gas ilustunune Gas Methods

January.....- 106 73 33 568
February..... 97 49 48 462
Marcha sng. 106 59 47 597
ATT ne ean: 116 51 65 749

ORs LG Ses eee 90 36 54 686
June eae 67 30 37 647
DY ics ats ievetens 57 20 37 634
INOP UA Gaal 64 23 41 603
September. ... 92 34 58 611
October... ... 144 77 67 655
November... .. 143 80 63 594
December. .... 149 92 57 541

ing than southern cities—and likewise produce annual varia-
tions according as the winters are mild or severe.

This table and the corresponding chart (Chart VI) disclose
many interesting and important details. December stands out
as the month of most deaths, and December is one of the months
of shortest days and longest nights as well as of lowest aver-
age temperature. It is therefore one of the times of greatest
use of gas, of most indoor life, and of least ventilation by open
doors and windows. It is not surprising that these condi-

ILLUMINATING GAS AND PUBLIC HEALTH 123

tions are correlated with the highest mortality from poisoning
by illuminating gas. What is remarkable is that the deaths
from this source were almost equally numerous in October
and November, although the days are then longer, the average
temperature considerably higher, and the possibility of com-
fortable sleeping with more open windows is much greater;

Cuart VI.

TTL I [etadodad obrpigution oF | [ | | | I |
[| [DEATHS FROM GAS RoIBoNINGIMaisachusetiTs] | | |
tit segueeeeeceee=

as
aS
a
nae
cian
ES
Res
p | |
HEE
ie
ss

Me
SOAR
Ee GS
RAGE e Ee
ae.
Be
ae oe teal
PEPER

Eee
Cees
BEee
Sraaas
aH

| A
pa A
y

ae January, which in mex of day and temperature closely
resembles December, shows fewer deaths than does December
from illuminating gas.

July, as might be expected, shows the smallest number of
deaths (57), June (67) and August (64) more, and each about
the same number, while September yields an increase of more
than 40 per cent. over June and over August. These facts
are not surprising when we reflect upon the cooler and longer

124 HARVEY SOCIETY

nights of June and August over those of July, and the much
cooler nights—often with frosts—of September over those of
June and of August. But beginning with October there is
no great difference in the deaths by months until we come to
January, when in spite of very cold weather and very short
days we find a marked decrease of deaths from poisoning by
illuminating gas, the deaths for January, February, March,
April, and May differing astonishingly Little.

We are aided in explaining these various figures by the
fact that April and October are the months of most numerous
suicides, not only by all methods (as shown by the last column
in Table 6 and by the corresponding thin, solid line, without
legend, on Chart VI), but also by illuminating gas; so that
the curve of total deaths by illuminating gas is necessarily
quite different from what it would be if it represented only
those deaths due to accident, and if accidents were solely due
to considerations correlated with the movement of the sea-
sons—such as temperature and length of days—and effective
ventilation. We find here, readily enough, a satisfactory ex-
planation of the large number of total deaths in October (144)
and November (143) as compared with December (149) when
the deaths from suicide (both by all methods and by gas)
were passing during these months from a maximum to a much
lower level. The fact appears to be that while the accidental
gas deaths were increasing during this quarter (as appears
in Table 6 and Chart VI and as would be required by theory)
the suicidal gas deaths were declining almost pari passu; so
that a remarkably even and high total of deaths from illuminat-
ing gas was maintained during this last quarter of the year.

In the next quarter (January-March) the gas suicides
were considerably fewer, as were also the deaths from acci-
dental gas poisoning, and very likely the same explanation
holds good of both these causes of death; namely, that condi-
tions had now become comparatively endurable, those that were
absolutely intolerable having already destroyed their victims
or having been changed for the better. The high number of

ILLUMINATING GAS AND PUBLIC HEALTH 125

total deaths in April appears to be chiefly due to the excess
of suicides in general characteristic of that month, as does
also the lower but still large number in May, when, as required
by theory, the seasonal conditions do not greatly favor acci-
dental gas poisonings and when, in fact—as shown by our fig-
ures—such poisonings are comparatively few.

It is also interesting to note, in passing, that upon Table 6,
and excepting in the first quarter, a close correspondence is
shown between the frequency of suicides by all methods and
those by illuminating gas.

THE RELATION OF CERTAIN COMBUSTION PRODUCTS OF ILLUMINAT-
ING GAS TO THE PUBLIC HEALTH

The principal combustion products of illuminating gas are
carbonic acid (CO,), water (H,O), light, and heat. Small,
but not insignificant amounts of ammonia, sulphurous acid,
soot, and other substances are also produced.

Carbonic acid, an inevitable product of all complete com-
bustion of carbon compounds, while not a desirable addition
to the atmosphere of a dwelling, a store, or a workshop, is
probably, unless present in very large quantities, of but little
consequence from the stand-point of health or comfort.

Water vapor, which is also copiously and inevitably pro-
duced in the ordinary combustion of illuminating gas, is prob-
ably of more importance than is carbonic acid to health and
comfort. Evidence of its abundant presence may often be
seen in the water upon the windows of shops, of stores, or of
living rooms, upon which it condenses freely and runs down,
sometimes almost in streams. The high humidity to which
this testifies is often prejudicial to the comfort, and probably
also to the health or working capacity, of the inmates.

The light produced by illuminating gas varies widely in
amount and composition. The old-fashioned coal-gas gave an
agreeable and apparently powerful yellowish light, and when
those who were accustomed to it began to be served with
water-gas, many found the latter bluish and less efficiently
luminous. Much here depends, no doubt, upon the special

126 HARVEY SOCIETY

form of burner, or ‘‘ tip ’’ employed, but after all is said and
done there are many—of whom the author is one—who, hay-
ing lived with both kinds of gas (and with many kinds of mix-
tures of the two) would gladly go back to the old-fashioned
coal-gas at double the present cost of gas, not only because of
its greater safety, but also because of its greater and more
agreeable illuminating effects.

As to the question of heat produced by combustion—a ques-
tion of great economic importance for those using gas as a
source of power, or for cooking or heating purposes, and of
much hygienic significance for persons occupying rooms lighted
by gas, it should be said that water-gas is not greatly superior
to coal-gas, while, since much heat is produced by the com-
bustion of either gas, their hygienic effects in this particular
are probably not very different. Electric lighting (although
open to other objections) is vastly preferable to gas lighting
on the score of heat production and that of objectionable chemi-
eal products.

Among the less abundant products of the combustion of
illuminating gas is sulphurous acid. Most coals used in the
manufacture of gas—and hence known as “‘ gas coals ’’—con-
tain a small percentage of sulphur, some of which appears
in illuminating gas as hydrogen sulphide and some as bisul-
phide of carbon, or other sulphur compounds. These, when
burned, formed sulphurous acid, an irritating and poison-
ous gas. Most of the sulphur compounds in illuminating gas
are, however, removed by processes of purification during
manufacture, but owing to the difficulty of complete removal,
20 grains of sulphur in every hundred cubic feet have gen-
erally been allowed by law to remain in the gas distributed
to the public. The 20-grain limit has prevailed in Great Bri-
tain for about half a century, and was apparently copied into
American statutes when legal regulation of the quality of il-
luminating gas was first undertaken—in Massachusetts, for
example, in 1861. And until quite recently no objection to
this legal limit has been raised by the gas manufacturers or

ILLUMINATING GAS AND PUBLIC HEALTH 127

by anyone else. A few years ago, however, the London gas
companies sought to have this sulphur regulation removed,
claiming that because the best gas coals are now scarce, it is
much more difficult than formerly to procure coals low in
sulphur, so that processes for the removal of sulphur have
become more costly and really burdensome to the industry of
gas manufacture. And after protracted hearings with the
taking of much testimony the sulphur restrictions were, in
fact, removed in England. A little later gas manufacturers
in the United States and in Canada came forward with a simi-
lar demand, and in Massachusetts the legal limit for sulphur
has now been raised from 20 grains to 30 grains per 100 cubic
feet of gas. A complete discussion of the whole subject of
the relation of the combustion products of sulphur compounds
in illuminating gas to the public health would require a mono-
graph. Suffice it to say that the testimony taken by the Brit-
ish Commission having the matter in charge, and by the Gas
Commissioners of Massachusetts (not to mention other authori-
ties) was voluminous, instructive, and important, and deserv-
ing of careful attention. It is the opinion of the author of the
present paper that the British authorities were not sufficiently
considerate of the public health aspects of the subject when
they allowed all restrictions upon the sulphur content of illu-
minating gas to be removed, and that the Massachusetts Gas
and Electric Light Commissioners acted more wisely when they
declined to follow the British example, and merely relaxed
somewhat the severity of the legal requirements regarding
sulphur.

Illuminating gas is required by law in Massachusetts (and
in many other places) to be free from ammonia as well as
from sulphuretted hydrogen, but this is more because of in-
jury to fixtures than because of danger to health.

THE PREVENTION OF POISONING BY ILLUMINATING GAS

The question naturally arises, What can be done for the

protection of the public health against poisoning by illuminat-
ing gas, which as a cause of sickness and death now almost

128 HARVEY SOCIETY

equals in Massachusetts and Rhode Island some of the dreaded
infectious and contagious diseases? We must admit at the
outset that about one-half of the recorded deaths from this
source are voluntary or suicidal, but while recognizing this
fact we have no right to dismiss it as irrelevant to the present
discussion. The State seeks, as far as possible, to prevent
suicide, by laws, for example, regulating the sale of other
poisons and of firearms, and may well regard with concern
the general distribution to the public of a dangerous gas readily
available for self-destruction.

Even more serious are the public consequences of the wide-
spread distribution to sick and well for industrial and do-
mestic purposes of a dangerous and highly poisonous sub-
stance, insidious in its mode of operation, quickly harmful in
its effects, and delivered under such pressure that leaks are
frequent. Those who have read and retlected upon the facts
given in the preceding sections will hardly need to be told how
prejudicial to the public health even small leaks of illuminat-
ing gas must be, especially if long continued, while the leakage
or escape of larger amounts is well known to be often fatal to
those exposed. The simplest and most natural remedy for
these evils would be, of course, to return to the former prac-
tice of making and distributing only coal-gas instead of water-
gas or a mixture of the two. But here, as so often in public
health problems, a balance must be struck between industrial
advantages accruing to the public in less cost, and some sav-
ing of life and health. If the industrial, economic, or efficiency
gain is very great, it may justify some increase of danger to
life and health. But if it is not very great, then life and
health have the prior claim. In the present case it is not
claimed that water-gas in Massachusetts or Rhode Island is,
as a rule, much if any cheaper to manufacture than is coal-
gas, but that it is very convenient to produce because more
quickly made when needed. The claims of the advocates of
water-gas in 1884 that this gas would furnish 24 candles of
light against the 16 candles of the old-fashioned ecoal-gas do

ILLUMINATING GAS AND PUBLIC HEALTH 129

not appear to have been substantiated, since most of the gas
now distributed in Massachusetts equals—according to the
State Inspector—only about 18 candles. The price of gas to
the consumer has, however, fallen greatly since 1884, and this
decrease in cost, as far as it is due to the use of water-gas,
must be balanced against the damage done to the public health
by the loss of more than 1200 lives and an unknown amount
of less obvious injury to life and health.

Undoubtedly a mixture of coal-gas and water-gas, such as
is often distributed to-day, is less dangerous than is water-
gas alone, but this appears to be merely because the dangerous
constituent, carbonic oxide, so abundant in water-gas, is diluted
by the process of mixture; and up to a certain point, the
greater the dilution, the less the danger. We know from ex-
perience that when carbonic oxide forms only about 6 per
cent. of illuminating gas very little danger exists. We also
know from experience that 20-30 per cent. of carbonic oxide
means danger. But whether 10 per cent. or perhaps 12 per
cent. might be allowed without much danger, we do not yet
know. It should, however, be possible to determine by experi-
ment the minimum amount safely allowable.

Meantime, in view of the appalling loss of more than 1200
lives which has occurred in Massachusetts since the 10 per
cent. restriction upon carbonic monoxide was removed, it seems
not unfair or unreasonable to demand a return to the 10 per
cent. limit until such time as evidence shall be forthcoming
that a higher percentage will properly safeguard the public
health.

A CONSIDERATION OF THE NATURE
OF HUNGER*

PROF. WALTER B. CANNON

Harvard University
LABORATORY OF PHYSIOLOGY IN THE HARVARD MEDICAL SCHOOL

HY do we eat?’’ This question, presented to a group
of educated people, is likely to bring forth the answer,
‘‘We eat to compensate for body waste, or to supply the body
with fuel for its labors.’’ Although the body is in fact losing
weight continuously and drawing continuously on its store of
energy, and although the body must periodically be supplied
with fresh material and energy in order to keep a more or less
even balance between the income and the outgo, this mainten-
ance of weight and strength is not the motive for taking food.
Primitive man, and the lower animals, may be regarded as
quite unacquainted with notions of the equilibrium of matter
and energy in the body, and yet they take food and have an
efficient existence, in spite of this ignorance. In nature, gen-
erally, important processes, such as the preservation of the
individual and the continuance of the race, are not left to be
determined by intellectual considerations, but are provided for
in automatic devices. Natural desires and impulses arise in
consciousness, driving us to action; and only by analysis do
we learn their origin or divine their significance. Thus our
primary reasons for eating are to be found, not in convictions
about metabolism, but in the experiences of appetite and
hunger.

APPETITE AND HUNGER

The sensations of appetite and hunger are so complex and
so intimately interrelated that any discussion is sure to go

* Delivered December 16, 1911. The results here stated were pub-
lished in the American Journal of Physiology, 1912, xxix, 441-454.
130

CONSIDERATION OF NATURE OF HUNGER 131

astray unless at the start there is clear understanding of the
meanings of the terms. ‘The view has been propounded that
appetite is the first degree of hunger, the mild and pleasant
stage, agreeable in character; and that hunger itself is a more
advanced condition, disagreeable and even painful—the un-
pleasant result of not satisfying the appetite.t On this basis
appetite and hunger would differ only quantitatively. Another
view, which seems more justifiable, is that the two experiences
are fundamentally different.

Careful observation indicates that appetite is related to
previous sensations of taste and smell of food. Delightful or
disgusting tastes and odors, associated with this or that edible
substance, determine the appetite. It has therefore important
psychic elements in its composition, as the studies by Pawlow
and his collaborators have so clearly shown. Thus, by taking
thought, we can anticipate the odor of a delicious beefsteak or
the taste of peaches and cream, and in that imagination we can
find pleasure. In the realization, direct effects in the senses
of taste and smell give still further delight. We now know
from observations on experimental animals and on human
beings, that the pleasures of both anticipation and. realization,
by stimulating the flow of saliva and gastric juice, play a highly
significant rdle in the initiation of digestive processes.”

Among prosperous people, supplied with abundance of
food, the appetite seems sufficient to ensure for bodily needs
a proper supply of nutriment. We eat because dinner is
announced, because by eating we avoid unpleasant consequences,
and because food is placed before us in delectable form
and with tempting tastes and odors. Under less easy cireum-
tances, however, the body needs are supplied through the
much stronger and more insistent demands of hunger.

The sensation of hunger is difficult to describe, but almost
every one from childhood has felt at times that dull ache or
gnawing pain referred to the lower mid-chest region and the
epigastrium, which may take imperious control of human
actions. As Sternberg has pointed out, hunger may be suffi-
ciently insistent to force the taking of food which is so dis-

132 HARVEY SOCIETY

tasteful that it not only fails to rouse appetite, but may even
produce nausea. The hungry being gulps his food with a
rush. The pleasures of appetite are not for him—he wants
quantity rather than quality, and he wants it at once.

Hunger and appetite are, therefore, widely different—in
physiological basis, in localization, and in psychic elements.
Hunger may be satisfied while the appetite still calls. Who
is still hungry when the tempting dessert is served, and yet
are there any who refuse it, pleading they no longer need it?
On the other hand, appetite may be in abeyance while hunger
is goading.2 What ravenous boy is critical of his food? Do
we not all know that ‘‘hunger is the best sauce’’? Although
the two sensations may thus exist separately, they nevertheless
have the same function of leading to the intake of food, and
they usually appear together. Indeed the co-operation of hun-
ger and appetite is probably the reason for their being so
frequently confused.

THE SENSATION OF HUNGER

In the present paper we shall deal only with hunger. The
sensation may be described as having a central core and certain
more or less variable accessories. The peculiar dull ache of
hungriness, referred to the epigastrium, is usually the organ-
ism’s first strong demand for food; and when the initial order
is not obeyed, the sensation is likely to grow into a highly
uncomfortable pang or gnawing, less definitely localized as it
becomes more intense. This may be regarded as the essential
feature of hunger, Besides the dull ache, however, lassitude
and drowsiness may appear, or faintness, or violent headache,
or irritability and restlessness such that continuous effort in
ordinary affairs becomes increasingly difficult. That these
states differ much with individuals—headache in one, and
faintness in another, for example—indicates that they do not
constitute the central fact of hunger, but are more or less
inconstant accompaniments, and need not for the present engage
our attention. The ‘‘feeling of emptiness,’’? which has been
mentioned as an important element of the experience,* is an

CONSIDERATION OF NATURE OF HUNGER 133

inference rather than a distinct datum of consciousness, and
ean likewise be eliminated from further consideration. The
dull pressing sensation is left, therefore, as the constant char-
acteristic, the central fact, to be examined in detail.

Hunger can evidently be regarded from the psychological
point of view, and discussed solely on the basis of introspec-
tion; or it can be studied with reference to its antecedents and
to the physiological conditions which accompany it—a con-
sideration which requires the use of both objective methods and
subjective observation. This psy chophysiological treatment of
the subject will be deferred till the last. Certain theories which
have been advanced with regard to hunger and which have been
given more or less eredit must first be examined.

Two main theories have been advocated. The first is sup-
ported by evidence that hunger is a general sensation, arising
at no special region of the body, but having a local reference.
This theory has been more widely credited by physiologists
and psychologists than the other. The other is supported by
evidence that hunger has a local source and therefore a local
reference. In the course of our examination of these views we
shall have opportunity to consider some pertinent new
observations.

THE THEORY THAT HUNGER IS A GENERAL SENSATION

The conception that hunger arises from a general condition
of the body rests in turn on the notion that, as the body uses
up material, the blood becomes impoverished. Schiff advocated
this notion, and suggested that poverty of the blood in food
substance affects the tissues in such manner that they demand
a new supply. The nerve-cells of the brain share in this
general shortage of provisions, and because of internal changes
give rise to the sensation.» Thus is hunger explained as an
experience dependent on the body as a whole.

Three classes of evidence are cited in support of this view:

1. ‘‘Hunger Increases as Time Passes’’—A Partial State-
ment.—The development of hunger as time passes is a common
observation which quite accords with the assumption that the

134 HARVEY SOCIETY

condition of the body and the state of the blood are becoming
constantly worse, so long as the need, once established, is not
satisfied.

While it is true that with the lapse of time hunger increases
as the supply of body nutriment decreases, this concomitance
is not proof that the sensation arises directly from a serious
encroachment on the store of food materials. If this argument
were valid we should expect hunger to become more and more
distressing until death. There is abundant evidence that the
sensation is not thus intensified; on the contrary, during con-
tinued fasting hunger wholly disappears after the first few
days. Luciani, who carefully recorded the experience of the
faster Succi, states that after a certain time the hunger feelings
vanish and do not return.®. And he tells of two dogs that
showed no signs of hunger after the third or fourth day of fast-
ing; thereafter they remained quite passive in the presence
of food. Tigerstedt, who also has studied the metabolism of
starvation, declares that although the desire to eat is very great
during the first day of the ordeal, the unpleasant sensations
disappear early, and at the end of the fast the subject may
have to force himself to take nourishment.‘ The subject,
‘‘J. A.,’’ studied by Tigerstedt and his co-workers, reported
that after the fourth day of fasting, he had no disagreeable
feelings. Carrington, after examining many persons who, to
better their health, abstained from eating for different periods,
records that ‘‘habit-hunger’’ usually lasts only. two or three
days and, if plenty of water is drunk, does not last longer than
three days.® Viterbi, a Corsician lawyer, condemned to death
for political causes, determined to escape execution by de-
priving his body of food and drink. During the eighteen days
that he lived, he kept careful notes. On the third day the
sensation of hunger departed, and although thereafter thirst
came and went, hunger never returned.'® Still further evidence
of the same character could be cited, but enough has already
been given to show that, after the first few days of fasting,
the hunger-feelings cease. On the theory that hunger is a
manifestation of bodily need, are we to suppose that, in the

CONSIDERATION OF NATURE OF HUNGER = 135

course of starvation, the body is mysteriously not in need
after the third day, and that therefore the sensation of hunger
disappears? The absurdity of such a view is obvious.

2. ‘“Hunger May be Felt Though the Stomach be Full’’—
A Selected Alternative-—Instances of duodenal fistula in man
have been carefully studied, which have shown that a modified
sensation of hunger may be felt when the stomach is full. A
famous case described by Busch has been repeatedly used as
evidence. His patient, who lost nutriment through the fistula,
was hungry soon after eating, and felt satisfied only when the
chyme was restored to the intestine through the distal fistulous
opening. As food is absorbed mainly through the intestinal
wall, the inference is direct that the general bodily state, and
not the local conditions of the alimentary canal, must account
for the patient’s feelings.

A full consideration of the evidence from cases of duodenal
fistula cannot so effectively be presented now as later. That in
Busch’s case hunger disappeared while food was being taken
is, as we shall see, quite significant. It may be that the restora-
tion of chyme to the intestine quieted hunger, not because
nutriment was thus introduced into the body, but because the
presence of material altered the nature of intestinal activity.
The basis for this suggestion will be given in due course.

3. ‘Animals May Eat Eagerly After Section of Their
Vagus and Splanchnic Nerves’’—A Fallacious Argument.—
The third support for the view that hunger has a general origin
in the body is derived from observations on experimental
animals. By severance of the vagus and splanchnic nerves, the
lower cesophagus, the stomach, and the small intestine can be
wholly separated from the central nervous system. Animals
thus operated upon nevertheless eat food placed before them,
and may indeed manifest some eagerness for it.1? How is this
behavior to be accounted for—when the possibility of local
peripheral stimulation has been eliminated—save by assuming
a central origin of the impulse to eat?

The fallacy of this evidence, though repeatedly overlooked,
is easily shown. We have already seen that appetite as well as

136 HARVEY SOCIETY

hunger may lead to the taking of food. Indeed the animal with
all gastro-intestinal nerves cut may have the same incentive
to eat that a well-fed man may have, who delights in the pleas-
urable taste and smell of food and knows nothing of hunger
pangs. Even when the nerves of taste are cut, as in Longet’s
experiments,'* sensations of smell are still possible, as well as
agreeable associations which can be roused by sight. More than
fifty years ago Ludwig pointed out that, even if all the nerves
were severed, psychic reasons could be given for the taking of
food,'* and yet because animals eat after one or another set of
nerves is eliminated, the conclusion has been drawn by various
writers that the nerves in question are thereby proved to be not
concerned in the sensation of hunger. Evidently since hunger
is not required for eating, the fact that an animal eats is no
testimony whatever that the animal is hungry, and therefore,
after nerves have been severed, is no proof that hunger is of
central origin.

Weakness of the Assumptions Underlying the Theory that
Hunger is a General Sensation.—The evidence thus far exam-
ined has been shown to afford only shaky support for the
theory that hunger is a general sensation. The theory further-
more is weak in its fundamental assumptions. There is no
clear indication, for example, that the blood undergoes, or has
undergone, any marked change, chemical or physical, when the
first stages of hunger appear. There is no evidence of any
direct chemical stimulation of the gray matter of the cerebral
cortex. Indeed attempts to excite the gray matter artificially
by chemical agents have been without results;'® and even
electrical stimulation, which is effective, must, in order to pro-
duce movements, be so powerful that the movements have been
attributed to excitation of underlying white matter rather than
cells in the gray. This insensitivity of cortical cells to direct
stimulation is not at all favorable to the notion that they are
sentinels set to warn against too great diminution of bodily
supplies.

Body Need May Exist Without Hunger—Still further
evidence opposed to the theory that hunger results directly

CONSIDERATION OF NATURE OF HUNGER 137

from the using up of organic stores is found in patients suf-
fermg from fever. Metabolism in fever patients is augmented,
body substance is destroyed to such a degree that the weight
of the patient may be greatly reduced, and yet the sensation
of hunger under these conditions of increased need is wholly
lacking,

Again if a person is hungry and takes food, the sensation
is suppressed soon afterward, long before any considerable
amount of nutriment could be digested and absorbed, and
therefore long before the blood and the general bodily condition,
if previously altered, could be restored to normal.

Furthermore, persons exposed to privation have testified
that hunger can be temporarily suppressed by swallowing in-
digestible materials. Certainly scraps of leather and bits of
moss, not to mention clay eaten by the Otomacs, would not
materially compensate for large organic losses. In rebuttal
to this argument the comment has been made that central states
as a rule can be readily overwhelmed by peripheral stimulation,
and just as sleep, for example, can be abolished by bathing the
temples, so hunger can be abolished by irritating the gastric
walls.1° That comment is beside the point, for it meets the
issue by merely assuming as true the condition under discussion.
The absence of hunger during the ravages of fever, and its
quick abolition after food or even indigestible stuff is swallowed,
still further weakens the argument, therefore, that the sensa-
tion arises directly from lack of nutriment in the body.

The Theory that Hunger is of General Origin Does Not
Explain the Quick Onset and the Periodicity of the Sensation.
—Many persons have noted that hunger has a sharp onset. A
person may be tramping in the woods or working in the fields,
where fixed attention is not demanded, and without premoni-
tion may feel the abrupt arrival of the characteristic ache.
The expression ‘‘grub-struck’’ is a picturesque description of
this experience. If this sudden arrival of the sensation corre-
sponds to the general bodily state, the change in the general
bodily state must oceur with like suddenness or have a critical
point at which the sensation is instantly precipitated. There

138 HARVEY SOCIETY

is no evidence whatever that either of these conditions occurs
in the course of metabolism.

Another peculiarity of hunger which I have noticed in my
own person, is its intermittency. It may come and go several
times in the course of a few hours. Furthermore, while the
sensation is prevailing, its intensity is not uniform, but marked
by ups and downs. In some instances the ups and downs change
to a periodic presence and absence without change of rate. In
making the above statements I do not depend on my own intro-
spection alone; psychologists trained in this method of observa-
tion have reported that in their experience the temporal course
gf the sensation is distinctly intermittent.* In my own experi-
ence the hunger pangs came and went on one occasion as
follows:

Came Went
12-37-20 38-30
40-45 41-10
41-45 42-25
43-20 43-35
44-40 45-55
46-15 46-30

and so on, for ten minutes longer. Again in this relation, the
intermittent and periodic character of hunger would require,
on the theory under examination, that the bodily supplies be
intermittently and periodically insufficient. Durimg one
moment the absence of hunger would imply an abundance of
nutriment in the organism, ten seconds later the presence of
hunger would imply that the stores had been suddenly reduced,
ten seconds later still the absence of hunger would imply a
sudden renewal of plenty. Such zig-zag shifts of the general
bodily state may not be impossible, but from all that is known
of the course of metabolism, such quick changes are highly
improbable. The periodicity of hunger, therefore, is further
evidence against the theory that the sensation has a general
basis in the body.

*T am indebted to Professor J. W. Baird, of Clark University,
and his collaborators, for this corroborative testimony.

CONSIDERATION OF NATURE OF HUNGER 139

The Theory that Hunger is of General Origin Does Not
Explain the Local Reference.—The last objection to this theory
is that it does not account for the most common feature of
hunger, namely, the reference of the sensation to the region of
the stomach. Schiff and others who have supported the
theory ** have met this objection by two contentions: First
they have pointed out that the sensation is not always referred
to the stomach. Schiff interrogated ignorant soldiers regard-
ing the local reference; several indicated the neck or chest,
23 the sternum, 4 were uncertain of any region, and 2 only
designated the stomach, In other words the stomach region
was most rarely mentioned.

The second contention against the importance of local
reference is that such evidence is fallacious. An armless man
may feel tinglings which seem to arise in fingers which have
long since ceased to be a portion of his body. The fact that he
experiences such tinglings and ascribes them to dissevered parts
does not prove that the sensation originates in those parts.
And similarly the assignment of the ache of hunger to any
special region of the body does not demonstrate that the ache
arises from that region. Such are the arguments against a
loeal origin of hunger.

Concerning these arguments we may recall, first, Schiff’s
admission that the soldiers he questioned were too few to give
conclusive evidence. Further, the testimony of most of them
that hunger seemed to originate in the chest or region of the
sternum cannot be claimed as unfavorable to a peripheral
source of the sensation. The description of feelings which
develop from disturbances within the body is almost always
indefinite. As Head and others have shown, conditions in a
viseus which give rise to sensation are likely not to be attributed
to the viscus, but to related skin areas.1* Under such cireum-
stances we do not dismiss the testimony as worthless merely
because it may not point precisely to the source of the trouble.
On the contrary, we use such testimony constantly as a basis
for judging internal disorders.

With regard to the contention that reference to the peri-

140 HARVEY SOCIETY

phery is not proof of the peripheral origin of a sensation, we
may answer that the force of that contention depends on the
amount of accessory evidence which is available. Thus if we
see an object come into contact with a finger, we are justified
in assuming that the simultaneous sensation of touch which
we refer to that finger has resulted from the contact, and is not
a purely central experience accidently attributed to an outlying
member. Similarly in the case of hunger—all that we need as
support for the peripheral reference of the sensation is proof
that conditions occur there, simultaneously with hunger pangs,
which might reasonably be regarded as giving rise to those
pangs.

OBJECTIONS TO SOME THEORIES THAT HUNGER IS OF LOCAL ORIGIN

With the requirement in mind that peripheral conditions be
adequate, let us examine the state of the fasting stomach to see
whether indeed conditions may be present in times of hunger
which would sustain the theory that hunger has a local out-
lying source.

Hunger Not Due to Emptiness of the Stomach—Among the
suggestions which have been offered to account for a peripheral
origin of the sensation is that of attributing it to emptiness
of the stomach. By use of the stomach tube Nicholai found
that when his subjects had their first intimation of hunger the
stomach was quite empty. But, in other instances, after lavage
of the stomach, the sensation did not appear for intervals vary-
ing between one and a half and three and a half hours.*® Dur-
ing these intervals the stomach must have been empty, and yet
no sensation was experienced. The same testimony was given
long before by Beaumont, who, from his observations on Alexis
St. Martin, declared that hunger arises some time after the
stomach is normally evacuated.” Mere emptiness of the organ,
therefore, does not explain the phenomenon.

Hunger not Due to Hydrochloric Acid in the Empty
Stomach.—A second theory, apparently suggested by observa-
tions on cases of hyperacidity, is that the ache or pang is due to
hydrochloric acid secreted into the stomach while empty. Again

CONSIDERATION OF NATURE OF HUNGER 141

the facts are hostile. Nicolai reported that the gastric wash-
water from his hungry subjects was neutral or only slightly
acid.2t. This testimony confirms Beaumont’s statement, and is
in complete agreement with the results of gastric examination
of fasting animals reported by numerous experimenters, There
is no secretion into the empty stomach during the first days of
starvation. Furthermore, persons suffering from absence of
hydrochlorie acid (achylia gastrica) declare that they have
normal feelings of hunger. Hydrochloric acid cannot therefore
be called upon to account for the sensation.

Hunger Not Due to Turgescence of the Gastric Mucosa.—
Another theory, which was first advanced by Beaumont, is
that hunger arises from turgescence of the gastric glands.”?
The disappearance of the pangs as fasting continues has been
accounted for by supposing that the gastric glands share in the
general depletion of the body, and that thus the turgescence
is relieved.* This turgescence theory has commended itself to
several recent writers. Thus Luciani has accepted it, and by
adding the idea that nerves distributed to the mucosa are spe-
cially sensitive to deprivation of food he accounts for the
hunger pangs.t Also Valenti declared two years ago that the
turgescence theory of Beaumont is the only one with a
semblance of truth in it.2* The experimental work reported
by these two investigators, however, does not necessarily sustain
the turgescence theory. Luciani severed the previously ex-
posed vagi after cocainizing them, and Valenti merely cocain-
ized the nerves; the fasting dogs, eager to eat a few minutes
previous to this operation, now ran about as before, but when
offered food, licked and smelled it, but did not take it. This
total neglect of the food lasted varying periods up to two

*A better explanation perhaps is afforded by Boldireff’s discovery
that at the end of two or three days the stomachs of fasting dogs
begin to secrete gastric juice and continue the secretion indefinitely.
(Boldireff: Archives biologiques de St. Petersburg, 1905, xi, p. 98.)

+ Luciani: Archivio di fisiologia, 1906, iii, p. 54. Tiedemann
long ago suggested that gastrie nerves become increasingly sensitive
as fasting progresses. (Physiologie des Menschen. Darmstadt, 1836,
iil, p. 22.)

142 HARVEY SOCIETY

hours. The vagus nerves seem, indeed, to convey impulses
which affect the procedure of eating, but there is no clear
evidence that those impulses arise from distention of the gland
cells. The turgescence theory, moreover, does not explain the
effect of taking indigestible material into the stomach. Accord-
ing to Pawlow, and to others who have observed human beings,
the chewing and swallowing of unappetizing stuff does not
cause any secretion of gastric juice.** Yet such stuff when
swallowed will cause the disappearance of hunger, and Nicholai
found that the sensation could be abolished by simply intro-
ducing a stomach sound. It is highly improbable that the
turgescence of the gastric glands can be reduced by either
of these procedures. The turgescence theory, furthermore, does
not explain the quick onset of hunger, or its intermittent and
periodic character. That the cells are repeatedly swollen and
contracted within periods a few seconds in duration is almost
inconceivable. For these reasons, therefore, the theory that
hunger results from turgescence of the gastric mucosa can
reasonably be rejected.

HUNGER THE RESULT OF CONTRACTIONS

There remain to be considered, as a possible cause of hunger-
pangs, contractions of the stomach and other parts of the
alimentary canal. This suggestion is not new. Sixty-six years
ago Weber declared his belief that ‘‘strong contraction of the
muscle fibers of the wholly empty stomach, whereby its cavity
disappears, makes a part of the sensation which we call hun-
ger.2> Vierordt drew the same inference twenty-five years later
(in 1871),?° and since then Ewald, Knapp, and Hertz have
declared their adherence to this view. These writers have not
brought forward any direct evidence for their conclusion,
though Hertz has cited Boldireff’s observations on fasting dogs
as probably accounting for what he terms ‘‘the gastrie con-
stituent of the sensation.’’ 27

The Empty Stomach and Intestine Contract.—The argument
commonly used against the gastric contraction theory is that the
stomach is not energetically active when empty. Thus Schiff

CONSIDERATION OF NATURE OF HUNGER 143

stated ‘‘the movements of the empty stomach are rare and much
less energetic than during digestion.’’** Luciani expressed his
disbelief by asserting that gastric movements are much more
active during gastric digestion than at other times, and cease
almost entirely when the stomach has discharged its contents.”
And Valenti stated only year before last, ‘‘we know very well
that gastric movements are exaggerated while digestion is pro-
ceeding in the stomach, but when the organ is empty they are
more rare and much less pronouneed,’’ and therefore they can-
not account for hunger.*°

Evidence opposed to these suppositions has been in exist-
ence for many years. In 1899, Bettmann called attention to the
contracted condition of the stomach after several days’ fast.**
In 1902, Wolff reported that after forty-eight hours without
food the stomach of the cat may be so small as to look like a
slightly enlarged duodenum.*? In a similar circumstance I
have noticed the same extraordinary smallness of the organ,
especially in the pyloric half. The anatomist His also recorded
his observation of the phenomenon.*® Six years ago Boldireff
demonstrated that the whole gastro-intestinal tract has a peri-
odie activity while not digesting.** Each period of activity
lasts from 20 to 30 minutes, and is characterized in the stomach
by rhythmic contractions 10 to 20 in number. These contrac-
tions, Boldireff reports, may be stronger than during digestion,
and his published records clearly support this statement. The
intervals of repose between periodic recurrences of the con-
tractions lasted from one and a half to two and a half hours.
Especially noteworthy is Boldireft’s observation that if fasting
in continued for two or three days, the groups of contractions
appear at gradually longer intervals and last for gradually
shorter periods, and thereupon, as the gastric glands begin
continuous secretion, all movements cease.

Observations Suggesting a Relation Between Contractions
and Hunger.—When Boldireft’s paper first appeared I was
studying auscultation of abdominal sounds, Repeatedly there
was occasion to note that the sensation of hunger was, as
already stated, not constant but recurrent, and that its momen-

144 HARVEY SOCIETY

tary disappearance was often associated with a rather loud
gurgling sound, as heard through the stethoscope. That con-
tractions of the alimentary canal on a gaseous content might
explain the hunger pangs seemed probable at that time, espe-
cially in the light of Boldireff’s observations. Indeed Boldi-
reff himself had considered hunger in relation to the activities
he described, but solely with the idea that hunger might pro-
voke them; and since the activities dwindled in force and
frequence as time passed, whereas, in his belief they should
have become more pronounced, he abandoned the notion of
any relation between the phenomena.*® Did not Boldireff
misinterpret his own observations? When he was considering
whether hunger might cause the contractions, did he not over-
look the possibility that the contractions might cause hunger?
A number of experiences have led to the conviction that Boldi-
reff did, indeed, fail to perceive part of the significance of his
results. For example, I have noticed the disappearance of a
hunger pang as gas was heard gurgling upward through the
eardia. That the gas was rising rather than being foreed down-
ward was proved by its regurgitation immediately after the
sound was heard. In all probability the pressure that forced
the gas from the stomach was the cause of the preceding sensa-
sion of hunger. Again the sensation can be momentarily abol-
ished a few seconds after swallowing a small accumulation of
saliva or a teaspoonful of water. If the stomach is in strong
contraction in hunger, this result can be accounted for as due
to the inhibition of the contraction by swallowing.*® Thus also
could be explained the prompt vanishing of the ache soon after
we begin to eat, for repeated swallowing results in continued
inhibition.* Furthermore, Ducceschi’s discovery that hydro-
chlorie acid diminishes the tonus of the pyloric portion of the
stomach *? may have its application here; the acid would be
secreted as food is taken and would then cause relaxation of the
very region which is most strongly contracted.

*The absence of hunger in Busch’s patient while food was being
eaten (see p. 135) can also be accounted for in this manner.

CONSIDERATION OF NATURE OF HUNGER 145

The Concomitance of Contractions and Hunger in Man.—
Although the evidence above outlined had led me to the con-
viction that hunger results from contractions of the alimentary
canal, direct proof was still lacking. In order to learn whether
such proof might be secured, one of my students, Mr. A. L.
Washburn, determined to become accustomed to the presence
of a rubber tube in the csophagus.* Almost every day for
several weeks Mr. Washburn introduced as far as the stomach a
small tube, to the lower end of which was attached a soft
rubber balloon about 8 em. in diameter. The tube was thus
carried about each time for two or three hours. After this
preliminary experience the introduction of the tube and its
presence in the gullet and stomach were not at all disturbing.
When a record was to be taken, the balloon, placed just below
the cardia, was moderately distended with air, and was con-
nected with a water manometer ending in a cylindrical chamber
3.5 em. wide. A float recorder resting on the water in the
chamber permitted registering any contractions of the fundus
of the stomach. On the days of observation Mr. Washburn
would abstain from breakfast, or eat sparingly; and without
taking any luncheon would appear in the laboratory about two
o’clock. The recording apparatus was arranged as above de-
scribed. In order to avoid the possibility of an artifact, a
pneumograph, fastened below the ribs, was made to record the
movements of the abdominal wall. Between the records of
gastric pressure and abdominal movement, time was marked
in minutes, and an electromagnetic signal traced a line which
could be altered by pressing a key. All these recording
arrangements were out of Mr. Washburn’s sight; he sat with
one hand at the key, ready whenever the sensation of hunger
was experienced to make the current which moved the signal.

Sometimes the observations were started before any hunger
was noted; at other times the sensation, after running a course,
gave way to a feeling of fatigue, Under either of these cir-

* Nicolai (loe. cit.) reported that although the introduction of a
stomach tube at first abolished hunger in his subjects, with repeated
use the effects became insignificant.

146 HARVEY SOCIETY

cumstances there were no contracticns of the stomach. When
Mr. Washburn stated that he was hungry, however, powerful
contractions of the stomach were invariably being registered.
As in the experience of the psychologists, the sensations were
characterized by periodic recurrences with free intervals, or
by periodic accesses of an uninterrupted ache. The record of
Mr. Washburn’s introspection of his hunger pangs agreed
closely with the record of his gastric contractions. Almost

dalla ai

LA isla

Fra. 1. One-half the original size. The top record represents intragastric pressure
(the small oscillations due to respiration, the large to contractions of the stomach); the
second record is time in minutes (ten seconds); the third record is Mr. Washburn’s report
of hunger pangs; the lowest record is respiration registered by means of a pneumograph
about the abdomen.

invariably, however, the contraction nearly reached its maxi-
mum before the record of the sensation was started (see Fig. 1).
This fact may be regarded as evidence that the contraction pre-
cedes the sensation, and not vice versa, as Boldireff considered
it. The contractions were about a half minute in duration and
the intervals between varied from 30 to 90 seconds, with an
average of about one minute. The augmentations of intra-
gastric pressure in Mr. Washburn ranged between 11 and 13 in

CONSIDERATION OF NATURE OF HUNGER 147

twenty minutes; I had previously counted in myself eleven
hunger pangs in the same time. The rate in each of us was,
therefore, approximately the same. This rate is slightly slower
than that found in dogs by Boldireff; the difference is perhaps
correlated with the slower rhythm of gastric peristalsis in man
compared with that in the dog.**

Before hunger was experienced by Mr. Washburn the re-
‘cording apparatus revealed no signs of gastric activity. Some-
times a rather tedious period of waiting had to be endured
before contractions occurred. And after they began they con-
tinued for a while, then ceased (see Fig. 2). The feeling of
hunger, which was reported while the contractions were recur-

x y * z

Fig. 2. One-half the original size. The same conditions asin Fig. 1. (Fifteen min-
utes.) There was a long wait for hunger todisappear. After z, Mr. Washburn reported
himself ‘‘tired but not hungry.”’ The record from y to z was the continuance on a second
drum of z to y.

ring, disappeared as the waves stopped. The inability of the
subject to control the contractions eliminated the possibility
of their being artifacts, perhaps induced by suggestion. The
close concomitance of the contractions with hunger pangs,
therefore, clearly indicates that they are the real source of those
pangs.

Boldireff’s studies proved that when the empty stomach is
manifesting periodic contractions, the intestines also are active.
Conceivably all parts of the alimentary canal composed of
smooth muscle share in these movements. The lower cesophagus
in man is provided with smooth muscle. It was possible to

148 HARVEY SOCIETY

determine whether this region in Mr. Washburn was active
during hunger.

To the csophageal tube a thin rubber finger-cot (2 em. in
length) was attached and lowered into the stomach. The little
rubber bag was distended with air, and the tube, pinched to keep
the bag inflated, was gently withdrawn until resistance was
felt. The air was now released from the bag, and the tube
further withdrawn about 3 cm. The bag was again distended

Fic. 3. One-half the original size. The top record represents compression of a thin
rubber bag in the lower esophagus. The pressure in the bag varied between 9 and 13 cm.
of water, The cylinder of the recorder was of smaller diameter than that used in the
gastric records, The cesophageal contractions compressed the bag so completely that, at
the summits of the large oscillations, the respirations were not registered. When the
oscillations dropped to the time line, the bag was about halfénflated. The middle line
registers time in minutes (ten seconds). The bottom record is Mr. Washburn’s report of
hunger pangs.
with air at a manometric pressure of 10 em. of water. Inspira-
tion now caused the writing lever, which recorded the pressure
changes, to rise; and a slightly further withdrawal of the tube
changed the rise, on inspiration, to a fall. The former position
of the tube, therefore, was above the gastric cavity and below
the diaphragm. In this position the bag, attached to a float-
recorder (with chamber 2.3 em. in diameter), registered the
periodic oscillations shown in Fig. 3. Though individually more
prolonged than those of the stomach, these contractions, it will

be noted, occur at about the same rate. It is probable that the

CONSIDERATION OF NATURE OF HUNGER 149

periodic activity of the two regions is simultaneous, for other-
wise the stomach would force its gaseous content into the
esophagus with the rise of intragastric pressure.

What causes the contractions to occur has not been deter-
mined. From evidence already given they do not seem to be
directly related to bodily need. Habit no doubt plays an im-
portant role. For present considerations, however, it is enough
that they do occur, and that they are abolished when food,
which satisfies bodily need, is taken into the stomach. By such
indirection, as already stated, are performed some of the most
fundamental of the bodily functions.

Peculiarities of Hunger Explained by Contractions.—lf
these contractions are admitted as the cause of hunger, most of
the difficulties confronting other explanations are readily
obviated. Thus the occurrence of hunger at meal times is most
natural, for, as the regularity of defecation indicates, the
alimentary canal has habits. Activity returns at the usual
meal time as the result of custom. By taking food regularly
at a definite hour in the evening for several days, a new hunger
period can be established. Since at these times the cesophagus
and the empty stomach strongly contract, hunger is aroused.

The contractions furthermore explain the sudden onset of
hunger and its peculiar periodicity—phenomena which no other
explanation of hunger can account for. The quick develop-
ment of the sensation after taking a cold drink is possibly
associated with the well-known power of cold to induce con-
traction in smooth muscle.

The great intensity of hunger during the first day of
starvation, and its gradual disappearance till it vanishes on the
third or fourth day, are made quite clear, for Boldireff observed
that the gastric contractions in his fasting dogs went through
precisely such alterations of intensity, and were not seen after
the third day.

In fever, when bodily material is being most rapidly used,
hunger is absent. Its absence is understood from an observa-
tion reported four years ago, that infection, with systemic
involvement, is accompanied by a total cessation of all move-

150 HARVEY SOCIETY

ments of the alimentary canal.*® Beldireff observed that when
his dogs were fatigued the rhythmic contractions failed to
appear. Being ‘‘too tired to eat’’ is thereby given a rational
explanation.

Another pathological form of the sensation—the inordinate
hunger (bulimia) of certain neurotics—is in accordance with
the well-known disturbances of the tonic imnervation of the
alimentary canal in such individuals.

Since the lower end of the cesophagus, as well as the stomach,
contracts periodically in hunger, the reference of the sensation
to the sternum by the ignorant persons questioned by Schiff
was wholly natural. The activity of the lower esophagus also
explains why, after the stomach has been removed, or in some
eases when the stomach is distended with food, hunger can still
be experienced. Conceivably the intestines also originate vague
sensations by their contractions. Indeed the final banishment
of the modified hunger sensation in the patient with duodenal
fistula, described by Busch, may have been due to the lessened
activity of the intestines when chyme was injected into them.

The observations recorded in this paper have, as already
noted, numerous points of similarity to Boldireff’s observations
on the periodic activity of the alimentary canal in fasting dogs.
Each period of activity, he found, comprised not only wide-
spread contractions of the digestive canal, but also the pouring
out of bile, and of pancreatic and intestinal juices rich in
ferments. Gastric juice was not secreted at these times; when
it was secreted and reached the intestine, the periodic activity
ceased.*? What is the significance of this extensive disturb-
ance? Recently evidence has been presented that gastric peri-
stalsis is dependent on the stretching of gastric muscle when
tonically contracted.41 The evidence that the stomach is in
fact strongly contracted in hunger—.e., in a state of high tone
—has been presented above.* Thus the very condition which

*The “empty” stomach and csophagus contain gas (see Hertz:
Quarterly Journal of Medicine, 1910, iii, p. 378; Mikuliez: Mittheil-
ungen aus dem Grenzgebieten der Medicin und Chirurgie, 1903, xii,
p. 596). They would naturally manifest rhythmic contractions on
shortening tonically on their content.

CONSIDERATION OF NATURE OF HUNGER 151

eauses hunger and leads to the taking of food is the condition,
when the swallowed food stretches the shortened muscles, for
immediate starting of gastric peristalsis. In this connection
the recent observations of Haudek and Stigler are probably
significant. They found that the stomach discharges its con-
tents more rapidly if food is eaten in hunger than if not so
eaten.*? Hunger, in other words, is normally the signal that
the stomach is contracted for action; the unpleasantness of
hunger leads to eating; eating starts gastric secretion, distends
the contracted organ, initiates the movements of gastric diges-
tion, and abolishes the sensation. Meanwhile pancreatic and
intestinal juices, as well as bile, have been prepared in the duo-
denum to receive the oncoming chyme. The periodic activity of
the alimentary canal in fasting, therefore, is not solely the
source of hunger pangs, but is at the same time an exhibition
in the digestive organs of readiness for prompt attack on the
food swallowed by the hungry animal.

BIBLIOGRAPHY

*Bardier: Richet’s Dictionnaire de Physiologie, article Faim, 1904,
vi, p- 1. See also, Howell: Text-book of Physiology, fourth
edition, Philadelphia and London, 1911, p. 285.

*Pawlow: The Work of the Digestive Glands, London, 1902, pp.
a0; 71.

* Sternberg: Zentralblatt fiir Physiologie, 1909, xxii, p. 653. Similar
views were expressed by Bayle in a thesis presented to the
Faculty of Medicine in Paris in 1816.

*Hertz: The Sensibility of the Alimentary Canal, London, 1911,
p. 38.

* Schiff: Physiologie de la Digestion, Florence and Turin, 1867, p. 40.

*Luciani: Das Hungern, Hamburg and Leipzig, 1890, p. 113.

"Tigerstedt: Nagel’s Handbuch der Physiologie, Berlin, 1909, i,
ps 376:

* Johanson, Landergren, Sonden and Tigerstedt: Skandinaviseches
Archiv fiir Physiologie, 1897, vii, p. 33.

*Carrington: Vitality, Fasting and Nutrition, New York, 1908,
p. 555.

*® Viterbi: Quoted by Bardier, loe. cit., p. 7.

“Busch: Archiy fiir pathologische Anatomie und Physiologie und
fiir klinische Medicin, 1858, xiv, p. 147.

152 HARVEY SOCIETY

* Schiff: loe. cit., p. 37. Also Ducceschi: Archivio di Fisiologia,
1910, viii, p. 579.

*Longet: Traité de Physiologie, Paris, 1868, i, p. 23.

“Ludwig: Lehrbuch der Physiologie des Menschen, Leipzig and
Heidelberg, 1858, 11, p. 584.

* Maxwell: Journal of Biological Chemistry, 1906-7, ii, p. 194.

* Schiff: loe. cit., p. 49.

* Schiff: loc. cit., p. 31. Bardier: loc. cit., p. 16.

* Head: Brain, 1893, xvi, p. 1; 1901, xxiv, p. 345.

* Nicolai: Ueber die Entstehung des Hungergefiihls. Inaugural-
Dissertation, Berlin, 1892, p. 17.

* Beaumont: The Physiology of Digestion, second edition, Burling-
ton, 1847, p. 51.

“Nicolai: loc. cit., p. 15.

“Beaumont: loe. cit., p. 55.

Valenti: Archives italiennes de Biologie, 1910, lu, p. 94.

* Pawlow: loc. cit., p. 70. Hornborg: Skandinavisches Archiv fiir
Physiologie, 1904, xv, p. 248.

* Weber: Wagner’s Handwérterbuch der Physiologie, 1846, iii’,
p. 580.

*° Vierordt: Grundriss der Physiologie, Tiibingen, 1871, p. 433.

* Knapp: American Medicine, 1905, x, p. 358. Hertz: loc. cit.,
p- 37.

** Schiff: loc. cit., p.. 33.

*® Luciani: loe. cit., p. 542.

* Valenti: loe. cit., p. 95.

* Bettmann: Philadelphia Monthly Medical Journal, 1899, 1, p. 133.

"Wolff: Dissertation, Giessen, 1902, p. 9.

* His: Archiv fiir Anatomie, 1903, p. 345.

“ Boldireff: Joe. cit., p. 1.

* Boldireff: loc. cit., p. 96.

* Cannon and Lieb: American Journal of Physiology, 1911, xxix,
p. 267.

* Duceeschi: Archivio per le Scienze Mediche, 1897, xxi, p. 154.

* Cannon: American Journal of Physiology, 1903, vili, p. xxi;
1905, xiv, p. 344. :

* Cannon and Murphy: Journal of the American Medical Associa-
tion, 1907, xlix, p. 840.

” Boldireff: loc. cit., pp. 108-111.

“Cannon: American Journal of Physiology, 1911, xxix, p. 250.

“FHaudek and Stigler: Archiv fiir die gesammte Physiologie, 1910,
CXxxili, p. 159,

THE CONTINUOUS ORIGIN OF CERTAIN
UNIT CHARACTERS AS OBSERVED
BY A PALEONTOLOGIST *

PROF. HENRY FAIRFIELD OSBORN
Columbia University.

NE method of ascertaining the height of a mountain

is with a single instrument, the barometer; another
method is by triangulation with several instruments. Thus
we may differ from Johannsen in his remark that morphology
as a science of great collections in museums is of no value in
genetics. The brilliant progress in heredity of the last nine
years, beginning in 1903 with the rediscovery of Mendel’s
law, should not blind us to the four broad inductions from
Paleontology,: that transformation is a matter of thousands or
hundreds of thousands of years, that to the living observer all
living things may be delusively stationary, that invisible tides .
of genetic change may be setting in one direction or another and
yet observable only over very long periods of time, that dis-
continuous mutations or saltations may be mere ripples on the
surface of these tides.

Whatever the truth as to these reflections, by a strange
paradox it is certain that some stationary characters, some
apparently dead things in the eyes of the zoologist and botanist,
become movable and alive in the eyes of the paleontologist.

Thus a paleontologist comes before the Harvey Society of
Physiologists and Physicians with the conviction that his vision
is of a different angle from that of the experimentalist, and that
by the triangulation of experiment, of anatomy and of paleon-
tology the truth may at least be more nearly approached.

* Delivered January 20, 1912.

*Osborn, Henry F., Darwin and Paleontology. One of the

addresses in Fifty Years of Darwinism. 8vo. Henry Holt & Co.,
New York, May 1, 1909.

153

154 HARVEY SOCIETY

The origin and history of ‘‘characters’’ is our quest, and now
that attention is concentrated all along the line of observation
in plants and animals, living and fossil, on the genesis and
behavior of single characters, we have laid the train of sub-
stantial progress. A vast gain is that which relegates the
problem of species to a side issue, or rather to an incidental
result of the accumulation and modification of a greater or
less number of units.

Among mammals a ‘‘character’’ may be racial shape of
head or length of limb, it may be a cusplet on a grinding tooth,
color of hair, or a sportive white lock of hair, it may be the
brown or blue color of the eye, it may be the speed of a horse,
or the obstinacy of a mule, in short, any structure or function,
simple or extremely complex, which is stable and distinct in
heredity. A ‘‘new character’’ is something which is unknown
before, it may be a new unit, like the horns of cattle, it may
be a new form or proportion of such a unit. ‘‘I understand by
the term unit character,’’ observes Morgan, ‘‘any particular
structure or function that may appear in heredity independent
of other characters. Such unit characters may in themselves
be extremely complex and include the possibility of further
splitting up.’? The point where Mendelism bears on the
problem is, therefore, in its bearing on the continuous or dis-
continuous origin of the thousands of characters which display
this more or less complete discontinuity in heredity.

Is there more evidence of discontinuity and of lawlessness,
or of continuity and of law, in the origin of such new charac-
ters? Perhaps no more appropriate question could be chosen as
the subject of a lecture in memory of William Harvey, the
author of the doctrine of epigenesis, for the essence of this
doctrine is that of ‘‘successive differentiation of a relatively
homogeneous rudiment into the parts and structures which are
characteristic of the adult.’? Paleontology is at one with
embryology in the belief that differentiation is in the main
gradual and continuous.

Yet, to our question, the answer prevailing among ex-
perimentalists and Mendelians at the present time is that

ORIGIN OF UNIT CHARACTERS 155

there is little evidence either for continuity or for law; this
despite the fact that a large part of the evidence for discon-
tinuity in the origin of characters is most unsound.

In fact, our first purpose in this Harvey Lecture is to
show how surprisingly unsound this evidence is when we
consider that discontinuity has become practically a dogma
among a very large number of zoologists and botanists.

It will appear that the evidence for discontinuity in the
heredity of characters is as convincing as that for discon-
tinuity in the origin of characters is most unsound.

Our second purpose in this Harvey Lecture is to show
that the evidence for continuity in the genesis of certain
characters in man and other mammals is very strong indeed,
further, that some of these characters, while apparently con-
tinuous in origin, certainly become discontinuous in heredity ;
from which it follows that discontinuity in heredity con-
stitutes no proof of discontinuity in origin.

How then do these manifold characters of which the body
is made up arise, continuously or discontinuously? <A con-
servative opinion from what may be gathered in the whole
field of observation at the present time is that while the
greater part of evolution is continuous, especially im the
origins of certain parts and in the development of certain
proportions, there must also be a discontinuity, especially
in numerical or meristic structures, such as vertebre and
teeth, and in chemical components and reactions which are
essentially antithetiec or discontinuous. In other words, there
is both continuity and discontinuity, and one problem is to
distinguish what is continuous from what is discontinuous.

I. EVIDENCES FOR DISCONTINUITY

Darwin has been widely misunderstood of late as believ-
ing in continuity,” whereas he chiefly believed in discontinuity.*

* Cf. Poulton, E. B.: Darwin and the “Origin,” 1909, pp. 49-50.
“His observation and study of nature led him to the conviction that
large variations, although abundant, were rarely selected, but that
evolution proceeded gradually and by small steps,—that it was ‘con-

156 HARVEY SOCIETY

In his original (1859) and final (1872) opinion evolution is due
chiefly to the selection of heritable ‘‘individual differences’’;
these have been understood by some as ‘‘fluctuations.’’ His
true meaning as to these individual differences is to be found
in the cases he cited, which may be collected from hundreds
of observations in the ‘‘Origin of Species’’ and ‘‘ Variation
of Animals and Plants under Domestication,’’ to the effect
that such individual differences or new characters were in the
nature of minor saltations, structural or functional, and
always hereditary. If we note some of the observations which
he assembled in commenting on the genesis of the race horse
and the greyhound, breeds which he used by way of illustration
of the genesis of new forms in nature, we find they include
such suddenly appearing new characters as horn rudiments,
taillessness, curliness of the hair, characters which are discon-
tinuous in Bateson’s sense, or mutations in that of De Vries;*
intermingled with these new characters he cited others which
are obviously reversional. That he believed in the adding up
of minor saltations there can be no question; but on the admir-
able ground that no evidence had been adduced in nature of
evolution by major saltations, he rejected St. Hilaire’s hypoth-
esis of the natural appearance of entirely new types of
animals and plants, or of new or profoundly modified organs;
there was no evidence in 1872 and there is none to-day of the
sudden appearance in nature of such a breed as the short-
legged Ancon sheep. Morgan remarks,® ‘‘ Darwin undoubtedly
supposed that by the continuous selection of minor saltations
a character could be slowly shifted in the direction of Selection.

tinuous’ and not ‘discontinuous.’” In answer to this opinion of the
most eminent British exponent of pure Darwinism it may be said
that small steps are discontinuities. (H. F. 0.)

“Osborn, H. F.: Darwin’s Theory of Evolution by the Selection
of Minor Saltations, Amer. Naturalist, vol. xlvi, No. 542, 1912, pp.
76-82.

“In 1909 L. Plate showed clearly that the “mutations” of De
Vries are practically identical with the “individual differences” of
Darwin. See Darwinismus und Landwirthschaft, Berlin, 1909.

°Morgan, T. H.: Letter, January 11, 1912.

ORIGIN OF UNIT CHARACTERS 157

This also appears to be the opinion of the conservative muta-
tionists of the present day.’’

Aside from his chief emphasis on the selection of ‘‘in-
dividual differences’? Darwin also undoubtedly believed in
the selection of heritable fluctuations of proportion as illus-
trated in his classic rebuttal of Lamarck in respect to the long
neck of the giraffe:

So under nature with the nascent giraffe, the individuals which
were the highest browsers, and were able during dearths to reach
even an inch or two above the others will often have been preserved;
for they will have roamed over the whole country in search of food.
These slight proportional differences will favor survival and will be
transmitted to offspring.

If, however, unusual length of neck in the giraffe, as in man,
is a saltatory and heritable fluctuation, there is no reason why
this classic case also may not strengthen the opinion that
Darwin was essentially a mutationist. Fluctuations of propor-
tion, the transmission of which is now in dispute, however,
formed a small part of Darwin’s scheme, nor was fluctuating
variability especially connected by him with the process of
evolution.

A very critical re-examination of Darwin’s works leads us,
therefore, to largely dissent from the influential opinion of De
Vries ° that there was always a doubt in Darwin’s mind as to
whether ‘‘the selection of mutations’’ or ‘‘the selection of ex-
treme variants’’ played the greater part in the origin of spe-
cies. As above noted, the actual cases which Darwin cited and
his repeated emphasis shows that minor saltations of the De
Vries type were chiefly in his mind.

It is obvious that Darwin could not draw such sharp dis-
tinctions either in language or in definition as we may to-day,
profiting by forty years of experiment and of analysis.

Let us therefore closely examine the kinds of saltation or
discontinuity in mammals which have been recorded during
the last fifty years by Darwin, Bateson, and others and see
what they signify.

*De Vries, Hugo: Die Mutationstheorie, Leipzig, 1901, p. 24.

158 HARVEY SOCIETY

1. Major and Minor Saltations in Mammals as Supposed
Material for Selection’

The above exposition of Darwin has a very direct bear-
ing on the problem of continuity and discontinuity because the
saltations which he believed to be among the possible materials

TABLE I
CoMPARATIVE TABLE OF SALTATIONS.

TYG Seg Fe Mk RST Re eae a aaa 8 x< x

. Absence of 1 horn on horned races.... . .

Jaw APPCOGABeS: <2 oche vee lacs kan oee x

. Taillessness, absence of caudals........ MIDE
. Earlessness, absence of the external ear.

. Single ears, loss of one ear............. x
10. Short-leggedness, or limb abbreviation. .
11. Consolidation of paired hoofs, syndactyl-

x
Supernumerary horns on horned races.. . XK
x
x

SOON DEACO tp

x
x

x
x
xX
x
x
x

12) Pobydsetylsmt. 2208 Gees ke ake aie las
13. Epidermal thickenings. ...............
14. Mottled skin markings................
15. Excessive hairiness, or length of hair... .
16. Hairlessness, entire absence of hair. ....
17. Excessively fine or silky hair........... x
18, CReversedshaltsncta iva clos oleinevnene tated

XXX X
XXXXX XX XX
x

Xx X

|X| X
x

x OK

20. Ourledshair eae ee eee Dix x x
x

of natural selection and of evolution were chiefly drawn from
the very same sources of evidence, namely, hybridization and
artificial conditions of environment, which are now drawn upon

'The writer is greatly indebted to Dr. Charles B. Davenport, of
the Carnegie Institution Station for Experimental Evolution, and to
Professor T. H. Morgan, of Columbia University, for eriticism and
suggestion on this section.

ORIGIN OF UNIT CHARACTERS 159

by the adherents of discontinuity; the only difference is one of
degree, not of kind. The great saltatory characters of Darwin
cited below (Table 1) in mammals are no more profound than
those cited by De Vries as composing the supposed ‘“‘elemen-
tary’’ species of @nothera. It is therefore interesting to com-
pare twenty distinct types or forms of major and minor salta-
tion in eleven different types of mammals. Our authorities
are Allen, Azara, Bateson, Brinkerhoff, Castle, Darwin, Daven-
port, Haecker, Percival, Poulton, Ridgeway, Root, Seton, Sut-
ton, Twining. The accompanying table presents at once the
very impressive result obtained by this comparison.

The very uniformity of the result makes us suspicious as
to the significance of saltations, major or minor, in evolution.
In eleven different kinds of mammals, namely, man, horses,
cattle, sheep, deer, pigs, dogs, cats, rabbits, guinea pigs, mice,
we observe that saltations exactly or closely similar repeatedly
occur. These saltations are of the same kind, in fact, they
partly include those which were regarded by Darwin as possi-
bly part of the evolution process through selection, namely, as
stable in inheritance and as under certain circumstances favor-
ing the animals which possessed them.

We evidently have to do with abnormal disturbances of
the germinal factors or determiners, Some of these saltations
are very stable in heredity and certain of them become wide-
spread; some are prepotent and dominant, others are recessive
(e.g., angora, or ‘‘long coat’’ in rabbits, Castle) ; some (e.g.,
bent tail in certain mice, Plate) follow neither the Mendelian
law nor the principle of blended inheritance.

On the unit-character doctrine we imagine that one of three
things may be happening in the germ plasm.

First, a ‘‘determiner’’ may drop out and we see a race of
mammals springing up without tails, or color, or hair. In
eattle the determiner for horns is dominant, therefore something
is added.

Second, a ‘‘determiner’’ may be suddenly lost or modified,
and we see excessive hair, curly hair, silky hair, dwarfed or
short limbs, brachydactylism.

160 HARVEY SOCIETY

Third, and even more inexplicable, there occurs the appear-
ance of a new ‘‘determiner”’ or the removal of an ‘‘inhibitor’’
and we observe horns suddenly arising on hornless races like
horses and rabbits.

That fancy breeds can be established through the abnormal
behavior and selection of these ‘‘determiners’’ there is no ques-
tion. That nature works through the sudden appearance of
new and favorable ‘‘determiners’’ is as yet unproved; it is
absolutely disproved in the case of horns, for through paleon-
tology we know that horns arise in a continuous manner. The
only mammal known to us at present in which it would appear
that a duplicate horn may have sprung into existence through
saltation is Tetraceros, the four-horned antelope of India.
Saltation is possibly of significance in the case of the sudden
alteration of hair character because we know of a very con-
siderable number of curly-haired horses in Mexico and South
America, which are, however, eliminated by breeders for the
reason that correlated with curliness of the hair are apt to
arise certain other characters in the hoofs and limbs which
are unfavorable.

Under wild or natural conditions in mammals we have
as yet secured no direct evidence of such origins or estab-
lishment of saltations either major or minor. There is reason
to believe that peculiar or anomalous mammals if they do
arise are driven away from the herds.

It would appear that the obvious abnormality of the
majority of these characters throws the remainder, as well as
saltatory new characters in general, under suspicion of
abnormality.

Paleontology, however, furnishes the most direct evidence
of the abnormality of saltations in such of the hard parts as are
enumerated in Table I by presenting counter evidence that
such profound changes as abbreviation of the face (prodpic
brachycephaly), development or loss of horns, reduction or
absence of caudal vertebrex, abbreviation or elongation of limbs,
syndactylism or consolidation of separate metapodials have all
been established, wherever we know their history, through
continuity and not through discontinuity.

ORIGIN OF UNIT CHARACTERS 161

2. Bateson’s Evidence (1894) for Discontinuity

Bateson in 1894 was the first to advance clearly the dis-
continuity hypothesis in its modern form as a mode of
origin of species. At the time his work appeared it suffered
a searching review from Scott.? Mutationists,’? however, still
refer to it as laying the foundations for the discontinuity
hypothesis. In order to test the ‘‘Materials for the Study of
Variation’”’ critically in the light of the subsequent advance
in paleontology, Dr. W. D. Matthew, who is without bias in the
question, was requested to examine all the cases of discontinuity
in mammals cited by Bateson with reference to the question
whether or not these cases have any real significance in evolu-
tion. He reports:

Of the 320 cases of discontinuity cited in mammals the greater
part are obviously teratological and have no direct significance in rela-
tion to paleontologic evolution except for a very few instanees such as
the supernumerary or fourth molar teeth of Otocyon. While not sig-
nificant [in evolution] these teratological cases are interesting because
they show the prevalence of homeosis, and indicate that many of the
remaining cases which might [otherwise] be considered normal salta-
tions or reversions may actually be teratologic, but disguised by
homeosis; all of the possibly significant cases (such as the supernu-
merary molars) are thereby placed under suspicion. Setting aside this
suspicion the minority of the “significant” cases in teeth and feet may
be said to afford evidence of the meristie variability of vestigial and
rudimentary structures. Bateson’s statement that such variability is
related not to non-functionalism but to terminal position in a series
appears to me directly in conflict with his [Bateson’s] own evidence,
as it certainly is with all my experience. This accords with commonly
observed data in paleontology, for no paleontologist would question
that vestigial teeth or bones are apt to [finally] disappear by “discon-
tinuous” evolution. As to the appearance by saltatory evolution of
new and primarily functional parts in teeth or feet, I know of no ade-
As pel aaa Se ES

*Bateson, Wm.: Materials for the Study of Variation Treated
with Especial Regard to Discontinuity in the Origin of Species,
Macmillan & Co., London, 1894.

* Scott, W. B.: On Variations and Mutations, Amer. Jour. Science
(3), vol. xlviii, 1894, pp. 355-374.

” Darbishire, A. D.: Breeding and the Mendelian Discovery, 8vo,
Cassell & Co., London, 1911.

162 HARVEY SOCIETY

quate paleontologic evidence in its favor. It is either demonstrably
false or decidedly improbable. In the cases of supernumerary teeth
(Otocyon myrmecobius, Cetacea, etc.) saltatory evolution may be re-
garded as reasonable in default of any paleontologic evidence to the
contrary. Meristic or numerical evolution in fully functional verte-
bre is intrinsically probable as the only method of evolutionary
change.

The fact that so many cases of supernumerary teeth are associated
with asymmetry throws doubt on the significance of all such cases;
asymmetric variations and those occurring only in upper or only in
lower teeth have no analogy in paleontology; such cases as occur ab-
normally are recognized as of a different and non-significant class than
normal evolutionary changes.

A summary of Matthew’s report is as follows:

Bateson cites 323 cases of discontinuity in vertebra, teeth
and skull. Of these 286 are abnormal, or teratological, or
reversional, and have absolutely no significance in evolution;
ten cases of supernumerary (or fourth molar) teeth are pos-
sibly significant because among the mammals there are a few
genera with fourth molars which may possibly have arisen by
saltation. There remain only thirty-seven cases which may be
ranked as ‘‘probably significant,’’ and these are the meristic
additions or reductions of vertebre in the spinal column,
significant because of the well-known numerical variations in
the vertebral formule of different mammals, and secondly be-
cause vertebre can be added or subtracted only discontinuously.

Summary or Barsson’s 323 Cases

ahi
I i
2 So SS
18 a go
0 i) 25
w 4 EL.
§ 2 'g6
Z & >
T;! * Vertebrate cicero cscs Ce aero 17 27°
(asymmetry)
TW Déethie eateries: oo eee eae 8 10t 67
DLT: CCH eres hsp a) os MAR Soroetee s sl coterie eee 110
210 37 67

* Numerical variations of cervical, dorsal and lumbar vertebre.
4 eee molars, cf. Octocyon, Myrmecobius, Cetacea. Six cases insufficiently
escribed.

ORIGIN OF UNIT CHARACTERS 163

The fact that the vast majority of germinal anomalies
examined in the above review of Darwin and of Bateson have
no significance in evolution in a state of nature, throws all
germinal anomalies under suspicion as natural processes,
important as they may be in artificial breeding and hybridiz-
ing. Yet some of these anomalies in mammals are less pro-
foundly discontinuous than those which De Vries has cited in
plants under the designation of ‘‘mutations.’’ The most
important of these De Vries’ mutations may now be considered.

3. Evidence for De Vries’ Mutation Theory

In 1901 the biological world was aroused, as it had not been
since 1859, by the publication of De Vries’ hypothesis."*

Here was a new and apparently sure foundation for discon-
tinuity in the supposed sudden appearance of elementary
species or ‘‘mutants’’ arising with the acquisition of entirely
new characters, new forms of plants or animals quite free from
their ancestors and not linked to them by intermediates. The
influence and vitality of this great work is shown in a citation
from Darbishire (1911, op. cit., p. 5):

The view that species have originated by mutation is based on Prof.
de Vries’ observations on the Evening Primrose (@nothera Lamarck-
tana) (Fig. 1). Working with this form, he was able to witness, for
the first time, the actual process of the origin of new species.

Critical analysis during the past two years by Davis and
by Gates’? of the very species @nothera Lamarckiana on
which De Vries chiefly based his monumental work, tends to
show that O. Lamarckiana is possibly a hybrid of O. biennis
and O. grandiflora and not a natural species. Thus the
“‘elementary species’’ which are springing from it in various

"De Vries, Hugo: Die Mutationstheorie, Leipzig, 1901, p. 24.

* Davis, Bradley Moore: Genetical Studies on Cinothera. II.
Some Hybrids of Gnothera biennis and O. grandiflora that resemble
O. Lamarckiana, Amer. Naturalist, vol. xlv, April, 1911, pp. 193-233.
Gates, R. R.: The Mutation Theory. The American Naturalist, vol.
xlv, No. 538, April, 1911, pp. 254-256. Mutation in Ginothera, Amer.
Naturalist, vol. xlv, No. 538, October, 1911, pp. 577-606.

164 HARVEY SOCIETY

gardens may prove to be comparable to the familiar results of
hybridization in mammals and birds.

Davis, on the basis of his prolonged experimental
researches, says (p. 193) :

Indeed, the theory of De Vries may fairly be said to rest chiefly
upon the behavior of this interesting plant, the account of which forms
so large a part of his work “Die Mutationstheorie” (2 vols., Leipzig,
(1901) ces

Gates makes the following statement (pp. 255-296) :

In a reperusal of the work one is struck by the optimism of
its author and the brilliancy and breadth of his exposition of the
views set forth. ... The analysis of the data amassed by Darwin,
in which it is shown that Darwin’s single variations are the same as
De Vries’ mutations, seems to the reviewer particularly effective. .. .
Probably the time will soon come when nearly all biologists will be
ready to admit that mutation, or the sudden appearance of new forms,
has been an important factor at least, in species formation of plants
and animals. Admitting this, it remains to be discovered what rela-
tion these sudden appearances bear to the general trends of evolution
which are apparent in so many phylogenies [italics our own]...
For, granting the facts of mutation, we have only accounted for micro-
evolution, and it is still to be shown that the larger tendencies can be
sufficiently accounted for by the same means, without the intervention
of other factors....

The skepticism of both these botanists is striking. Their

opinions as to the existence of larger evolutionary trends are
exactly in accord with those of paleontologists.

4. Evidence for Discontinuity from Mendehan Heredity
and Experimental Selection

The newest bulwark of the discontinuity hypothesis is that
erected since 1903 by the revival of the great discovery of
Mendel (1865) and by the negative results of experiments on
fluctuating or quantitative variation.

From the prevalence of discontinuity in heredity, the
separateness of ‘‘unit characters’’ as they appear in the body
and the equally sharp separableness of their complex of ‘‘fac-
tors,’’ ‘‘determiners’’ or ‘‘genes’’ in the germ has arisen the
purely theoretical assumption of the discontinuity of origin of

ORIGIN OF UNIT CHARACTERS 165

all characters in the germ. We shall attempt to show that this
assumption is a non-sequitur.

First, however, the truly marvellous and epoch-making
Mendelian discoveries require our special examination in their
bearing on the problem of continuity and discontinuity. We
have reviewed 2* the contributions of Allen, Bateson, Castle,
Cannon, Cuénot, Darbishire, Davenport, Durham, Farrabee,
v. Guita, Haacke, Hagedoorn, Harmon, Hurst, Laughlin, Mor-
gan, Pearson, Plate, Punnett, and Rosenoff. This review
covers unit characters only as observed in mammals, to which
none the less the principles discovered by Mendel in the
common garden pea (Pisum sativum) apply with striking
uniformity.

The prevailing field of the researches of these talented
investigators in mammals has been in color characters, chemical
in essence, in various species of rodents, chiefly mice and
guinea pigs, also in Ungulates, such as horses and cattle, the
latter studied less by experiment than from stud books. Hair
form in rodents and in man and skin pigment have also been
exactly investigated. The most striking general result is the
principle of antithesis of characters which mutually exclude
each other, as typified by the antithesis of Mendel’s ‘‘tallness’”’
and ‘‘shortness’’ in peas.

The second great result is that when these antithetic
characters meet in the germ cells, one dominates over the other ;
this dominance is a sort of perpetual prepotency. ‘‘Prepo-
tency,’’ observes Darbishire, ‘‘is an attribute of individuals
and capricious in its appearance... . Whatever be the nature
of this power .. . it is clear that it has nothing to do with
dominance .. . dominance is an invariable attribute of particu-
lar characteristies.’’?* Plate (1910), on the contrary, observes,
“But a variety of facts seem to indicate that a reversal of
dominance may occur under certain circumstances and a domi-

EE Lice AER AS a
* With the aid of Miss Mary M. Sturgess, now attached to the
Carnegie Institution Station for Experimental Evolutions at Cold
Spring Harbor, L. I.
* Darbishire: op. cit., p. 96.

166 HARVEY SOCIETY

nant character may become recessive, and vice versa.’’*> Such
reversal of dominance would appear to be the case in a com-
parison of the mule (cross between ass ¢' and horse 2 ) and
the hinny (cross between the horse 6’ and the ass @ ).

When antithetic characters or functions meet in heredity,
there is either ‘‘prepotency,’’ or ‘‘dominance,’’ or ‘‘recession”’
(i.e., latency), or ‘‘inhibition,’’ a something which indirectly
prevents the appearance of characters, or ‘‘imperfect domi-
nanee,’’ of ‘‘blending.’’ In brief, there are degrees of separa-
bleness and antithesis.

Dominance, Conservative or Progressive—tlt will be seen
at once that progressive evolution through discontinuity would
depend on the dominance of racially new characters and types.

The experimental evidence is conflicting, it does not show
that new characters are necessarily dominant.

There are many instances of dominance of wild species
(older type) over domesticated species (newer type); thus
De Vries suggested (1902) that the dominant characters are
those which are racially older. One case among the mammals
is that the wild gray color in mice dominates over grades below
it, black, brown, and white (Plate, 1910).

Examples of dominance in single characters are that more
intense dominate over less intense colors (Plate, 1910, Daven-
port, 1907); in the eyes, brown over gray, gray over blue; in
the skin, brunettes over blondes (Davenport, 1909), piebalds
over pure albinos (Plate, 1910); in the hair, wavy or spiral
forms dominate over straight (Davenport, 1908). These facts
of experiment are directly opposed to the natural fading out
of color in desert races like the quagga, which lost all the
stripes of its intensely colored relative the zebra.

The idea that the positive or present character dominates
over the negative, latent or absent character has become a
prevailing one.

It seems highly probable, observes Davenport (1910), that the fu-
ture will show that many more advanced or progressive conditions are
really due to one or more unit-characters not present in the less ad-

ye * Plate.

ORIGIN OF UNIT CHARACTERS 167

vanced condition. In that case it will appear that there is a perfect
accord in the two statements that the progressive and the “present”
factor are dominant (pp. 89-90) .. . the specific characteristies are
mostly those that appear late in ontogeny (p. 86) ... the potency
of a character may be defined as the capacity of its germinal deter-
miner to complete its entire ontogeny. If we think of every character
as being represented in the germ by a determiner, then we must recog-
nize the fact that this determiner may sometimes develop fully, some-
times imperfectly and sometimes not at all [italics our own]... .
When such a failure occurs in such a normal strain a sport results.
. . . Potency is variable. Even in a pure strain a determiner does
not always develop fully and this is an important cause of individual
variability (Davenport, 1910, p. 92).

Plate similarly favors the hypothesis of dominance of newer
or progressive characters. He observes (1910):

The [Mendelian] laws of inheritance favor progressive evolution in
two ways, for... higher, more complicated characters are generally
dominant to the lower, and .. . qualitative characters usually follow
the Mendelian principle in the ease of closely related forms (races,
varieties), while in the crossing of species they follow intermediate [or
blended] inheritance as a rule. In the latter case there is the pos-
sibility that the crossing may have a swamping effect, but this can
play no large réle on account of the infrequency of hybrids between
species (Plate, 1910, p. 606).

Plate is of the opinion that phyletie evolution is discon-
tinuous as regards the transformations of the determinants
[determiners], but in most cases is continuous in their visible
outward workings. He thus maintains that while germinal
transformations are discontinuous there may be no real
antithesis between continuous and discontinuous somatic
variation.

Mendelians appear to agree, first, that there are grades of
continuity and discontinuity, that there are antithetic characters
which are sharply discontinuous, others which are partly con-
tinuous, blended or intermediate. Second, some new characters
are dominant, others are recessive. Third, it would appear that
complete discontinuity or entire dominance or recession are
qualities in heredity which may gradually evolve. Many
characters show imperfect dominance (Castle, 1905) ; gametic
purity is not absolute (Castle, 1906) ; selection is of importance

168 HARVEY SOCIETY

in the improvement of races (Castle, 1907). There are a num-
ber of truly blending characters, such as lop-earedness in
rabbits (Castle, 1909); cross blends of long and short hairs .
(Castle, 1906), cross blends between short- and lopeared rabbits
which are permanent (Castle, 1909), blends in weight inherit-
ance and in skeletal proportion (Castle, 1909).

Recent work has led to the opinion (Hatai, 1911)** that
blended inheritance may be considered to be a limited ease of
alternative inheritance where dominance is imperfect; Mendel’s
law of alternative inheritance may be considered as the standard
in all the cases referred to it (Hatai, 1911, p. 106). Certain
characters which were considered formerly to blend are now
regarded as showing a certain kind of segregation or unit
inheritance. Thus Davenport (1909) observes:

Skin pigment does not show thorough blending inheritance, but
segregation (sometimes imperfect), a more pigmented being imper-
fectly dominant over a less.” ... The reason, the same author
observes (1909), for the blending of hair and skin color in man is the
non-development of distinct color unit-determiners owing to the fact
that in man for a long period there has been no selection for
intensity of color, whereas in the lower mammals definite color
determiners have long been maintained by selection.

Thus the prevalent recent opinion or hypothesis among
Mendelian observers is that there is a real discontinuity between
the germinal or blastic characters and what the paleontologist
or morphologist generally observes, is only an apparent con-
tinuity between somatic characters.

Since, however, the behavior of visible or somatic characters
forms our only means of knowing whether the determiners
are continuous or discontinuous, it is obvious that this opinion
or rather this ingenious hypothesis requires further examina-
tion and experiment.

* Hatai, Shinkishi: The Mendelian Ratio and Blended Inheritance,
Amer. Naturalist, vol. xlv, No. 530, February, 1911, pp. 99-106.

Piomentation of the skin seems to depend in man on a series of
color intensity units, possibly one or a few large units, more probably
a number of small units so close together as to be almost continuous
(Davenport, 1910).

ORIGIN OF UNIT CHARACTERS 169

5. Johannsen’s Pure Line Theory}®

The hypothetical contrast between a real discontinuity of
the blastic determiners and a delusive continuity of visible or
somatic form is pushed to its extreme in the ‘‘pure-line’’ con-
ception which marks the latest development in heredity, an
advance upon Weismann’s germ-plasm theory and Mendel’s
unit-character law. Through experiments on successive genera-
tions of self-fertilizing plants (the garden bean), Johannsen
has reached a standpoint which may be briefly stated as
follows:

A “pure line” is composed of the descendants of one pure strain
or homozygotie organism exclusively propagated by self fertilization;
such pure lines demonstrate the stability of hereditary constitution in
successive generations where undisturbed by cross breeding or ming-
ling with other strains, showing that the only real changes in organ-
isms are those due to the sudden appearance of new determiners in the
germ.

To replace the word determiner the term gene is proposed. The
genotype represents the sum total of all the genes in the fertilized
germ cell, gamete or zygote; we do not know a venotype, but we are
able in experiment to demonstrate “genotypical differences.” The
biotype is a group of similar genotypes or pure strain individuals.

Gene, genotype, and biotype are not seen; they are the smaller and
larger units of heredity.

The phenotype is what we see; it is the developing organism.
Morphology supported by the huge collections of the museums has
operated with “phenotypes” in phylogenetic speculation. It is thus
a science of phenotypes and is not of value in genetics because pheno-
type description is inadequate as the starting point for genetic in-
quiries. The adaptation of phenotypes through the direct influence of
environment [Buffon’s factor] or of use and disuse [Lamarck’s fac-
tor] is not of genetic importance. Ontogenesis is a function of the
genotype, but the genotype is not a function of ontogenesis. The idea
of evolution by continuous transitions from one type to another has
imposed itself upon zoologists and botanists, who are examining chiefly
shifting phenotypes in very fine gradations. There is such a econtinu-
ity in phenotypes but not in the genotypes from which they spring.
All degrees of continuity between phenotypes may be found, but real
genetic transitions must be distinguished from the transitions which
we find in museums.

* Johannsen, W.: The Genotype Conception of Heredity, Amer.
Naturalist, vol. xlv, No. 531, March, 1911, pp. 129-159.

170 HARVEY SOCIETY

Genotypes, it is true, can only be examined by the qualities and re-
actions of the phenotypes.

Such examination shows that within pure lines—if no new muta-
tions or other disturbances have been at work—there are no geno-
typical differences in the characters under examination. The only real
discontinuity is that between different genotypes. The mutations ob-
served in nature have shown themselves as considerable discontinuous
saltations. There is no evidence for the view that mutations are prac-
tically identical with continuous evolution. In pure lines no influence
of special ancestry ean be traced; all series of progeny keep the geno-
type unchanged through long generations. Discontinuity between
genotypes and constant differences between the genes show a beautiful
harmony between Mendelism and pure line work.

Selection will have no hereditary influence in changing genotypes.
Even the selection of fluctuations in pure lines is ineffective to produce
a new genotype.

Heredity may thus be defined as the presence of identical genes in
ancestors and descendants, or heredity stands for those properties of
the germ cells that find expression in the developing and developed
phenotype.

Jennings observes:

What distinguishes the different genotypes, then, is a different
method of responding to the environment. And this is a type of
what heredity is; an organism’s heredity is its method of respond-
ing to the evironmental conditions [p. 84]... . It appeared clear, and
still appears clear, that a very large share of the apparent progressive
action of Selection has really consisted in the sorting over of pre-
existing types, so that it has by no means the theoretical significance
that had been given to it [p. 88]... . I had hoped to accomplish this
myself, but after strenuous, long-continued and hopeful efforts, I
have not yet succeeded in seeing Selection effective in producing a
new genotype. This failure to discover Selection resulting in
progress came to me as a painful surprise, for like Pearson I find
it impossible to construct for myself a “philosophical scheme of evolu-
tion,” without the results of Selection, and I would like to see what
I believe must oceur [pp. 88-89]. . . . It would seem that the diverse
genotypes must have arisen from one, in some way, and when we
find out how this happens, then such Selection between genotypes
will be all the Selection that we require for our evolutionary progress
[p. 89].

Johannsen’s general conception of the origin of progressive
or retrogressive new characters is that ‘‘it is sufficient to state

that. the essential point in evolution is the alteration, loss or

ORIGIN OF UNIT CHARACTERS 171

gain of the genes or constituents of the genotypes .. . all
evidences as to ‘mutations’ point to the discontinuity of the
changes in question.”’

6. Negative Results of Experiments on Quantitative Variation

We agree with Johannsen that an appearance of continuity
might arise through the selection of degrees of hereditary
fluctuation in structure or function, for example, of tallness
or shortness of stature, of intensity or faintness of color. This
brings up the problem of fluctuation in the germinal de-
terminers. Some Mendelians discard fluctuations altogether as
non-hereditary; thus Punnett (1911, p. 138)?® observes: ‘‘At
the present time we have no valid reason for supposing that
they [fluctuations] are ever inherited.”’

The problem, however, is not as to quantitative ontogenic
variations caused by favorable or unfavorable environment or
by changes or habit, but as to heritable fluctuations springing
from the germ plasm. Experiments have been directed to the
point whether variations in size, in proportion, etc., of heredi-
tary unit characters are transmitted and accumulated by
selection.

Davenport also has reached negative results; he observes
(1910) :

In the last few decades the view has been widespread that char-
acters can be built up from perhaps nothing at all by selecting in
each generation the merely quantitative variation that goes farthest
in the desired direction. The conclusion upon which De Vries laid
the greatest stress, that quantitative and qualitative characters differ
fundamentally in their heritability, is supported by our experiments
(p. 96). I have made two tests of this view using the plumage color
of poultry (p. 94). ... After three years of selection of the reddest
offspring no appreciable increase of the red was observed except in
one case, which looks like a sport (p. 96). These fluctuating quanti-
tative conditions depend on variations in the point at which the
ontogeny of the character is stopped; and the stopping point is in
turn often if not usually determined by external conditions which
favor or restrict the ontogeny. Thus the selection of redness of comb,
of polydactylism, of syndactylism, have not proven the inheritance of
quantitative variations. Apparently, within limits, these quantitative

* Punnett, R. C.: Mendelism, Macmillan Co., 1911 (3d edition).

172 HARVEY SOCIETY

variations have so exclusively an ontogenie signification that they are
not reproduced so long, at least, as environmental conditions are not
allowed to vary widely.

Similarly Love 7° from experiments on the yielding power
of plants remarks:

Unless further studies produce different results we can say from
the facts at hand that there is no evidence to show that a basis exists
for cumulative selection.

Similar conclusions have been reached by Pearl (1909) ”*
in the breeding of fowls for laying purposes.

All the above results are negative.

Even the positive or affirmative results obtained by Cuénot
and later by Castle, wherein quantitative characters may be
shifted in one direction or the other by selection, are now given
a new interpretation by certain Mendelians.

On the other side Cuénot showed by continued selection of
lighter colored mice that the coat became paler; and Castle has
shown that in rats the coat through selection may be made
darker. Castle remarks (1911) :*

I prefer to think with Darwin that selection . . . can heap up
quantitative variations until they reach a sum total otherwise un-
attainable, and that it thus becomes creative.

He cites cumulative results in the development of a
fourth toe in the hind foot of guinea-pigs and in the
modification of the dorsal striping of hooded rats.

Morgan’s remarks (1912) on these positive experiments
are as follows:

Castle has been very guarded in regard to the interpretation of the
results of selection in this case. It is probable that extreme selection

* Love, Harry H.: Are Fluctuations Inherited? Contr. VI, Lab.
Experim. Plant-Breeding, Cornell Univ., Amer. Naturalist, vol. xliv,
No. 523, July, 1910, pp. 412-423.

“Pearl, Raymond: Is there a Cumulative Effect of Selection
Abstammungs und Verebungslehre, 2, 1909, H. 4.

™ Castle, W. E.: The Nature of Unit Characters, The Harvey Lec-
tures, delivered under the Auspices of the Harvey Society of New
York, 8vo, J. B. Lippincott Co., pp. 90-101.

ORIGIN OF UNIT CHARACTERS 173

is necessary to maintain the higher stage reached. It does not breed
true and slips back easily. If this is correct it suggests: first, that
nothing permanent has been effected in the germ-cells; and second,
that the result is due to the discovery of more extreme cases of
fluctuating variations than ordinarily occur.

The general import of these experiments and opinions 7s
that fluctuations in the determiners, or genes, can be
utilized to establish a new quantitative mean. It is obvious
that what have been measured by biometricians as hereditary
‘“fluctuations’’ might be regarded as ‘‘saltations’’ of all de-
grees, but such saltations do not represent new determiners in
the Mendelian or Johannsen sense; they are mere fluctuations
in existing determiners. Pure Mendelians would allege that
tallness in man or other mammals can only be accumulated
‘through the saltatory origin of ‘‘tall’’ determiners which are
not connected continuously through intermediate forms with
the antithetic ‘‘short’’ determiners. As to stature Brownlee
observes (1911, p. 255) : 78

I think that I have shown that there is nothing necessarily antago-
nistic between the evidence advanced by the biometricians and the
Mendelian theory. ... (1) If the inheritance of stature depends upon
a Mendelian mechanism, then the distribution of the population as
regards height will be that which is actually found, namely, a distri-
bution closely represented by the normal curve.

6. Summary as to Discontinuity and Mendelism

Genetics is the most positive, permanent and triumphant
branch of modern biology. Its contributions to heredity are
epoch-making. But heredity is the conservative aspect of
biology, and experimental genetics thus far chiefly reveals the
laws of conservation rather than of natural progression.

Genetics has not yet brought us one single step nearer the
solution of the problem of the progressive origin of new char-

* Brownlee, J.: The Inheritance of Complex Growth Forms, such
as Stature, on Mendel’s Theory, Proce. Roy. Soc. Edinburgh, vol. xxxi,
Pt. II, 1911, pp. 251-256.

174 HARVEY SOCIETY

acters in mammals. The very independence, multiplicity and
discontinuity of the units leave us farther afield. In place of
what used to be regarded as the instability of the organisms, as
a whole, we now have to conceive of the instability of thou-
sands, nay hundreds of thousands of units.

As shown in our analysis of the saltations cited by Darwin
and Bateson, Mendelism has revealed the fact that the majority
of saltations simply refiect failures in the germinal mechanism.
The inference is natural that the remaining minority also
represent anomalies, or lawless conditions. Over a half century
of anatomical research among mammals in a state of nature
has failed to demonstrate the sudden origin of a single new
progressive character which has become fixed in the race.

Nor have Mendelism and experimentalism released us from
the hard confines of examination of the germ through the
soma; behavior of unit characters in the soma is the sole means
of knowing the behavior of the ‘‘determiners’’ in the germ.
If the unit characters in the soma behave discontinuously we
are forced to the conclusion that their determiners behave dis-
continuously ; if, on the contrary, these unit characters behave
continuously, are we not forced to the conclusion that there
is a continuity in the behavior of the corresponding determiners?

Let us therefore proceed to consider the value of some of
the evidence for continuous behavior in the germinal origin of
certain new somatic characters, again repeating our opinion
that certain other characters are essentially antithetic, without
intermediates, and consequently discontinuous both in
heredity and in origin.

JI. EVIDENCES FOR CONTINUITY

Abandoning the historical background, we come to our own
subject, the origin and establishment in continuity of certain
characters which when established exhibit many of the dis-
tinctive features of unit characters, namely, segrega-
tion, stability, pure heredity, and possibly, although this has
not yet been demonstrated, dominance and recession in suc-
cesswe generations.

ORIGIN OF UNIT CHARACTERS 175

1. Rectigradations and Allometrons.

In fifteen previous papers by the writer beginning in 1889**
the observation is repeatedly made that all absolutely new
characters which we have traced to their very beginnings in
fossil mammals arise gradually and continuously. One by one
these characters, which are independently changing in many
parts of the organism, at the same time accumulate until they
build up a degree of change which paleontologists designate
as a ‘‘mutation’’ in the sense of Waagen, who proposed this
inter-specific term in 1869; finally these new characters attain
a sufficiently important phase to designate the stage as a
species.”°

These new characters were first (1891) termed ‘‘definite
variations’’; subsequently (1907)?* the term “‘rectigradations”’
was applied to them.

Rectigradation is merely a designation for the earliest dis-
cernible stages of certain absolutely new characters; it involves
no opinion nor hypothesis as to genesis; it is a simple matter
of observation. Referring to the figure (p. 200) of the upper
grinding teeth of the horse, the majority of the fourteen char-
acters have been observed to arise as rectigradations.

Quite different is the allometron. This is a new designation
for the continuous change of proportion in an existing char-
acter which may be expressed in differences of measurement.
Since 1902 and especially during the past year the behavior

* Osborn, H. F.: The Paleontological Evidence for the Transmis-
sion of Acquired Characters, Amer. Naturalist, vol. xxiii, No. 271,
July, 1899, pp. 561-566.

* This sentence may be contrasted with that of Punnett (op. cit.,
p. 15): “Speaking generally, species do not grade gradually from one
to the other, but the differences between them are sharp and specific.
Whence comes this prevalence of discontinuity if the process by which
they have arisen is one of accumulation of minute and almost imper-
ceptible differences? Why are not intermediates of all sorts more
abundantly produced in nature than is actually known to be the case?”

* Osborn, H. F.: Evolution of Mammalian Molar Teeth to and
from the Triangular Type, 8vo, Macmillan Company, September, 1907.

176 HARVEY SOCIETY

of allometrons has been very carefully investigated by myself
and by my colleague, Dr. W. K. Gregory.

RECTIGRADATION —a qualitative change, the genesis
of a new character in an adap-
tive direction.

ALLOMETRON =a quantitative change, the genesis
of new proportions in an ex-
isting character.

The distinction between a rectigradation and an allometron
is readily grasped: when the shadowy rudiment of a cusp or of
a horn first appears it is a rectigradation; when it takes on a
rounded, oval or flattened form this change is an allometron.
In mammals rectigradations are comparatively few and in-
frequent, while allometrons comprise the vast number of changes
in the hard parts. In the origin of cusp and horn rudiments
rectigradations are parallel or convergent (see Fig. 3), in the
changing proportions of a skull allometrons are divergent
(Figs.-1, 3).

Granting, without at present considering the evidence,”
that these rectigradations and allometrons arise continuously
through entirely unknown laws, also that they are blastic or
germinal characters, the question arises, Do they become sepa-
rable as unit or alternating characters in heredity?

In general, paleontology furnishes quite as strong proof
as Mendelism or experimental zoology as to the individuality,
separableness, and integrity of single characters in evolution.
But, whether both rectigradations and allometrons are separable
in heredity can only be demonstrated through experiments on
eross breeding or hybridizing.

The special object of this Harvey Lecture is to show that
certain at least of the rectigradations and allometrons observed
in mammals are separable in heredity, that they split up into
larger and smaller groups or units, some into partially blend-

7 This evidence is for the first time fully presented in the writer’s
monograph on the “ Titanotheres,” in preparation for the U. 8S.
Geological Survey.

ORIGIN OF UNIT CHARACTERS 177

ing units, others into absolutely distinct or non-blending units;
finally that at least in the first cross they exhibit dominance.
The very important remaining question whether, like the
quality of ‘‘tallness’’ or ‘‘shortness’’ in Mendel’s classic experi-
ments on the pea, these allometrons continue to split into
- dominants and recessives in later crosses, has not been investi-
gated, but is probably capable of investigation in mammals
which do not become sterile in the first hybrid generation.

Fig. 1. Continuous ORIGIN or ALLOMETRIC ‘‘ UNIT CHARACTERS’ IN THE
; CRANIUM (A) AND SKULL (B) oF MAN AND TITANOTHERES.

A, Man Brachycephaly Mesaticephaly Dolichocephaly
B, Titanotheres Brachycephaly Mesaticephaly Dolichocephaly
(Paleosyops) (Manteoceras) (Dolichorhinus)

Five examples of the continuous evolution of rectigrada-
tions and allometrons may be cited, namely:
. Skull and horns of titanotheres (Figs. 1, 3, 4).
The horns of eattle (Fig. 2).
. The cranium of man (Fig. 1).
. The skull of horses (Figs. 4, 5, 6, 7).
5. Teeth (Fig. 8).

178 HARVEY SOCIETY

One of the most salient examples of the genesis of unit
characters through continuity is that of the evolution of horns,
v.€., of the osseous prominences on the skull. Horns are now
known definitely to be ‘‘unit characters,’’ first through their
sudden and complete disappearance in the niata and polled
breeds of cattle; second, because they conform to the laws of
sex-limited inheritance. The pertinent question is, Do horns
originate continuously or discontinuously ?

2. Horns of Titanotheres

The titanotheres are an extinct family of quadrupeds dis-
tantly related to the horses, tapirs and rhinoceroses, to the
evolution of which the author has devoted twelve years of
investigation, assisted by Dr. W. K. Gregory. As set forth in
an earlier contribution ** the genesis of horns as rectigrada-
tions has been observed in four or five distinct phyla of titan-
otheres. These phyla descend independently from a single
ancestor of remote geologic age. Both in respect to new cusps
on the teeth and new horn rudiments on the skull there is
observed what in our ignorance may be ealled an ancestral
predisposition to the genesis of similar rectigradations. This
predisposition betrays the existence of law in the origin of
certain new characters; it recalls a sagacious remark of Darwin:

... The principle formerly alluded to under the term of analogical
variation has probably in these cases often come into play; that is,
the members of the same class, although only distantly allied, have in-
herited so much in common in their constitution, that they are apt to
vary under similar exciting causes in a similar manner; and this
would obviously aid in the aecquirement through natural selection of
parts or organs, strikingly like each other, independently of their
direct inheritance from a common progenitor.”

Briefly, the history of the origin of the titanothere horns

*The Four Inseparable Factors of Evolution. Theory of Their
Distinct and Combined Action in the Transformation of the
Titanotheres, an Extinet Family of Hoofed Animals in the Order
Perissodactyla, Science, N. S., vol. xxvii, No. 682, January 24, 1908,
pp. 148-150.

” Origin of Species, vol. ii, p. 221.

ORIGIN OF UNIT CHARACTERS 179

is as follows: (a) from excessively rudimentary beginnings, 7.e.,
rectigradations, which can hardly be detected on the surface
of the skull; (b) there is some predetermining law or similarity
of potential which governs their first existence, because (c)
the rudiments arise independently on the same part of the
skull in different phyla at different periods of geologic time;
(d) the horn rudiments evolve continuously, and they grad-
ually change in form (2. e., allometrons); (e) they finally be-
come the dominating characters of the skull, showing marked
variations of form in the two sexes; (/) they first appear in late
or adult stages of ontogeny, but are pushed forward gradually
into earlier and earlier ontogenic stages until they appear to
arise prenatally.

In the titanotheres (Fig. 3) the bony swelling is seen at
the junction of the nasals and frontals (black shading), in
dolichocephalic skulls it appears chiefly on the nasals, in
brachycephalic skulls chiefiy on the frontals. Its original low,
rounded shape is like that seen in the ontogeny of the horns
in cattle (Fig. 2).

3. Horns of Cattle

The phylogenesis of the horns in titanotheres (Fig. 3) is
exactly similar to the ontogenesis of the horns in Bovide
(Fig. 2), in which the dermal rudiments first appear soon after
the complete formation of the bones of the skull in the unborn
young, and the osseous rudiments appear as rounded pro-
tuberances in the 8th month.

In the ontogenesis of horns in cattle three distinct elements
are involved: (a) a psychic predisposition to use the horn, (0)
a dermal thickening over the bony horn region which in
ontogeny precedes the bony swelling, (c) appearance of the
bony swelling itself.

The ontogenesis is observed to be accompanied by a marked
allometric change in the skull which shifts the horn back-
ward from the side of the cranium to the side of the occiput
by the obliteration of the parietal bones (Fig. 2).

HARVEY SOCIETY

180

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ORIGIN OF UNIT CHARACTERS 181

4. Cranium of Man

A third instance of continuous development is that of the
form of the cranium in man (Fig. 1), an allometric evolution,
or change of proportion, which is of especial significance be-
cause, according to the unanimous testimony of anthropolo-
gists,°° head form is the result of very gradual change either
in the elongate (dolichocephalic) or broadened (brachyce-
phalic) direction.

The matter is directly pertinent to the present discussion
because human ‘‘long heads’’ and ‘‘broad heads’’ are con-
tinuously crossing and we know what the direction and ultimate
effects of such crosses are. The evidence has important
theoretical bearing also on the influence of selection, environ-
ment, and inheritance or the effects of use and disuse.

Determination of the proportions of the cranium or the
cephalic index is one of the standard tests of race; it is an
expression of the greatest breadth of the head above the ears
and the percentage of its greatest length from the forehead
(glabella) to back, the latter measurement being taken as 100.
Three types adopted by anthropologists are:

Extreme Range

Brachycephalic, 80.1 and above ..........-sseee-- 100-80
NPE IEC FOE OO! We a bisralefe in cla icc a cgca's wiere tie sscatp 80-75
Dolichocephalic, 75 and below ........--++esseeeee 75-62

Among the present races of Europe the widest limits of
variation between brachycephaly and dolichocephaly are in the
averages between 73 and 87; individual extremes of 62 and 100
have, however, been observed. These extremes in Huropean
head form do not coincide either with geographic or political
boundaries, but are attributed to the entrance into Europe of
brachycephalie and dolichocephalie types which evolved in Asia.

Similarly among the aborigines of America the indices range
from a low dolichocephaly as among the Delaware, Pima
Indians, ete., to a decided brachycephaly as among the

Ripley, Wm. Z.: The Races of Europe, a Sociological Study, 8vo,
D. Appleton & Co., 1899, 624 pp.

182 HARVEY SOCIETY

Athabasean tribes in Panama, Peru, and other localities. A
significant fact in Europe is that dolichocephaly and brachy-
cephaly are extremely stable characteristics in heredity.
The significant fact again is that through a very long period
of time the various races of Indians, who are believed to have
had originally a similar origin, have acquired under conditions
of geographic isolation considerable diversity in the propor-
tions of the head.

Similarly A. Keith *t from the present distribution of the
Negro tribes in equatorial Africa has reached the following
conclusions :

There has been free intermigration; in the course of their evolu-
tion, the tendency of one tribe has been towards the accentuation of
one set of characters, of another towards another set. Thus the
Dinka acquire high stature and narrow heads; the typical Nigerians
low stature and narrow heads; the Basoko wide, short heads and low
stature; the Buruns wide heads and high stature. Interbreeding may
have played its part; but if it had played a great part we should have
found greater physical uniformity than there is. The influence of
Arab blood on these tribes has probably been exaggerated.

It appears that environment has not any direct influence
on head form, but that geographical isolation affords the sev-
eral varieties of man as well as other mammals a chance to
develop their peculiar head characters. Thus Elliot Smith
states (letter, August 12, 1911):

In my opinion the conditions of dolichocephaly and brachycephaly
must have developed very slowly through exceedingly long periods of
time and in widely separated areas amidst widely different environ-
ments. Brachycephaly is especially distinctive of the Central Asian
high plateau populations, dolichocephaly of the littoral and plain-
dwelling peoples; but these “unit characters” are now so fixed that
environment is powerless to modify them in a thousand years or so.
... 1 do not believe for a moment in Boas [that is, in Boas’s observa-
tions (1911) on the rapid influence of environment in modifying head
form].

"Keith, A.: Journ. Royal Anthropological Institute, 1911. See
Nature, vol. 88, No. 2195, November 23, 1911, p. 119.

ORIGIN OF UNIT CHARACTERS 183

Elliot Smith takes very strong ground as to the lack of
evidence that environment directly produces any modification
of head form; he implies that such modification, if natural,
would only show itself after thousands of years of residence;
environment no doubt has indirect influence. Hrdlicka, on
the other hand, believes he has obtained definite results in
the influence of environment [or habit, H. F. O.] on the vault
and face form of the Eskimo;** it remains to be shown how far
these changes are ontogenic. The recent conclusions of Boas
(1911)** that dolichocephaly and brachycephaly are congeni-
tally altered by environment in the first generation are modified
by his statement that this action in bringing diverse head forms
together would not go so far as to establish a uniform general
type.

No anthropologist has offered any satisfactory explanation
as to the adaptive significance of dolichocephaly or brachy-
cephaly. It is well known that these differences of head form
are not associated with intellectual ability or mental aptitude.
Boas writes (April 8, 1911):

So far the matter is very perplexing to me. I feel, however, very
strongly with you that changes in type are very liable to be progres-
sive in definite directions. . . . To my mind it seems no more difficult
to assume that this predetermined direction should continue from
generation to generation than to make the much more difficult assump-
tion that notwithstanding all internal changes the egg-cell of one
generation should be absolutely identical with that of the preceding
generation.

Apart from the disputed problems of the direct influence
of environment and of human selection there is absolute
unanimity of evidence and of opinion on the one point essential
to the present discussion, namely, as to the continuity of

* Hrdlicka, Ales: Contribution to the Anthropology of Central and
Smith Sound Eskimo, Anthr. Paper Am. M. N. H., v, Pt. IL, 1910,
p. 214.

*® Boas, Franz: The Mind of Primitive Man, 8vo, Maemillan Com-
pany, New York, 1911, 924 pp.

184

HARVEY SOCIETY

ee ee

III

Fig. 3. RectTiGRADATIONS AND ALLOMETRONS IN TITANOTHERES. Continuity in the
phylogenesis of osseous hornsin titanotheres. P= 2d lower premolar; H = section of nasals
and frontals (shaded) showing osseous horn; S = skulls; M = median metacarpal bones.

Vie
IV.
III.
1a
if

Dolichorhinus, a long-headed (dolichocephalic) titanothere.
Manteoceras, a medium-headed (mesaticephalic) titanothere.
Telmatherium, a medium-headed (mesaticephalic) titanothere.
Paleosyops, a broad-headed (brachycephalic) titanothere.
Eotitanops, an ancestral (mesaticephalic) titanothere.

II-V belong to four independent phyla which diverge in their allometric evolution of
head (S) and foot proportion (M) but give rise to independent similar rectigradations in the
origin of cusps on the premolar teeth (P) and of osseous horn rudiments (#) on the skull.

ORIGIN OF UNIT CHARACTERS 185

allometric variation which establishes different extremes of
head form under conditions of geographic isolation.

Granted that such extremes as dolichocephaly and
brachycephaly evolve continuously, do they become discon-
tinuous in heredity?

One of the general results of crossing long-headed and
narrow-faced types with broad-headed and broad-faced types
is what is known as disharmonic heredity, namely, that condi-
tion in which the face and cranium do not hold together, but
broad faces may couple with long skulls, or vice versa (Boas,
1903).°* Boas concludes that there can be no question that the
mixture of a long-headed and of a short-headed race may lead
to disharmonism, one race contributing head form, the other
facial proportion.

As to stability or segregation in heredity the latest opinions
of Boas, Elliot Smith and Hrdlicka have been sought. Boas
is one of the most positive as to the herditary stability of head
form. He observes (1911, pp. 7-9):

Among European peoples head proportions are considered among
the most stable and permanent of all characteristics. In intermarriage
of “dolichocephalic” and “brachycephalic” individuals the children
do not form a blend between their parents but inherit either the
dolichocephalie or brachycephalic head form. Head form thus econ-
stitutes a case of almost typical alternating heredity (p. 55). No evi-
dence has been obtained, however, to show that either brachycephaly
or dolichocephaly is dominant. Children exhibit one head form or the
other, and the cephalic index or ratio of breadth to length undergoes
only slight alteration during growth, or ontogeny.

Elliot Smith (letter of August 12, 1911) is ‘‘firmly econ-
vineed that the form of cranium, orbits, nose, jaws, limb bones,
ete., in the ‘Armenoid’ and ‘Proto-Egyptian’ series are very
stable or even fixed ‘unit characters’ which do not really blend,
but that certain elements of a mosaic assemblage of characters
may be grafted on to others belonging to the other race.’’

Opinions as to Blending—It will be noted, however, that

“Boas, Franz: Heredity in Head Form, Amer. Anthropologist,
vol. 5, No. 3, July-September, 1903, pp. 530-538.

186 HARVEY SOCIETY

Boas (1895) admits a certain blending of head form in crosses.
Hrdli¢cka (letter, November 1, 1911) speaks even more
guardedly as to the hereditary stability of head form. He says:

As to the head form constituting a “unit character” which does not
blend in intermixture, I am not able to give a conclusive opinion, but
my experience and other considerations lead me to be very skeptical
that such is the case to any great extent. The subject is a very com-
plex one and requires considerable direct investigation in different
localities and with different peoples before the exact truth can be
known. ... As to the statement that long or broad head form is a
stable or unit character not blending in intermixture, I think that only
the first part of the proposition may be held as fairly settled. But
even then I should change the word “stable” to “persistent,” and
qualify the phrase by adding “under no greatly differing and lasting
environmental conditions.”

That prolonged interbreeding or intermixture tends to
break down the stability of hereditary head form is indicated
by Boas, Elliot Smith, and Ripley, as well as by Hrdlicka, as
quoted above. Thus Ripley (1899, p. 55) observes:

The plotting of cephalic indices on a map of Europe shows that
there is a uniform gradation of head form from several specific
centres of distribution outward.

In Italy over 300,000 individuals taken from every little
hamlet have been measured. In the extreme south we find
the dolichocephalic head form of the typical Mediterranean
race; the type changes gradually as we go north until in
Piedmont we find an extreme of brachycephaly in the Alpine
type, recalling the broad-headed Asiatic type of skull. Thus
(Ripley, p. 56) ‘‘pure physical-types come in contact and this
means ultimately the extinction of extremes.’’ Applying these
principles to the present case, it implies the ultimate blending
of the long and the narrow heads and the substitution of one
of medium breadth.

Elliot Smith also (letter, August 12, 1911) implies a grad-
ual modification or blending of head form through prolonged
intermixture. He observes:

ORIGIN OF UNIT CHARACTERS 187

Egypt does not give a clear answer to your queries because her ex-
ceedingly dolichocephalic brown race [related to the Mediterranean
race of southern Europe] underwent a double admixture (cirea
3000 B.c.) with moderately brachycephalic “ Armenoids” from Asia

Brontother.™

Opisthopic
Dol.

Proopic
Dol.

Eohippus

Fie. 4. Continuous OrI@In oF ALLOMETRICc ‘‘ Unit CHARACTERS’’ IN THE SKULL OF
Various UNGULATES.

C, Cytocephaly Bubalis Rangifer
D, Dolichocephaly Opisthopic Proépic
(Titanotheres) (Equines)

In the ancestral Eotitanops and Eohippus the facio-cranial index is very similar. In
the descendants of these animals, as indicated by the dotted lines, the facio-cranial indices
are widely divergent; in the Titanotheres (Brontotherium) the cranium is elongated; in
the horses (Equus) the face is elongated.

and dolichocephalie Negroes from Africa. The Mediterranean Egyp-
tians are on the whole a little broader-headed than they were 6,000
years ago, and this may be due in part to a slow development toward
mesaticephaly; but it is mainly the result of an admixture with alien

188 HARVEY SOCIETY

bracephalies and mesaticephalies. There is an unquestionable tendency
toward the elimination of the extremes of narrowheadedness and
broadheadedness.

Hrdlitka (letter, December 5, 1911) observes:

As to the effect of the mixture of brachyeephalic and dolicho-
cephalic individuals or peoples, I am led to believe that there is in the
results of such mixtures a large percentage of more or less intimate
“blend” of the two forms, for such a condition is indicated by the
eurves of distribution of the cephalic index among such national
conglomerates as the French, Germans, different tribes of the Amer-
ican Indians, ete. These curves, if sufficiently large numbers of
individuals have been examined, all approach more or less the ideal
eamel-back curve. If no “blend” existed, we should be bound to get
the double or dromedary-back curve. Of course the effects of mixture
and the effects of environment are with our present means often
impossible of separation, they often obscure each other. Yet the
indications are that there is generally a considerable amount of more
or less mixture of the many elementary constituents of the hereditary
characters [known collectively as] dolichocephaly and brachycephaly.
With this there coexists doubtless some tendency toward a differentia-
tion into the two opposite forms of the head.

Thus in human head form we have strong evidence of con-
tinuous allometric change strictly comparable to that which
occurs in the crania of lower mammals, especially as observed
in the horses and titanotheres; the extremes are produced in
so-called pure human races under conditions of geographic
isolation; when these pure races are brought together there
arises disharmonism or alternating heredity or both. Neither
the dolichocephalic nor brachycephalic type is as yet known
to be dominant; while opinion is divided as to whether in the
first cross the heredity is pure or whether there may be a
tendency to produce an intermediate form, opinion is nearly
unanimous that prolonged interbreeding produces blends.*®

* TH. Morgan observes that a blend may occur in the first genera-
tion, F'1, even where perfect segregation occurs in F2. The results of
crossing the equine skull as described below indicate a tendency to
blend certain characters in the first cross.

ORIGIN OF UNIT CHARACTERS 189

5. Skull of Titanotheres

The continuity of allometric evolution in the skull of the
titanotheres (Fig. 4) has been the subject of prolonged inves-
tigation by the writer, assisted by Dr. W. K. Gregory, involv-
ing thousands of measurements, many of which belong in
strictly successive phyletic series. Allometry (i.e., the meas-
urement of allometrons) here applies to the skull as a whole.
We secure the cephalic index by dividing the breadth across
the cheek arches by the total basilar length of the skull. There
are also other indices, such as the facio-cranial, in which we
measure continuous trends of allometric change. Brachycephaly
and dolichocephaly arise independently in four different phyla
or lines of descent. The adaptive significance is sometimes
apparent, sometimes obscure. As shown in Fig. 1 the titan-
otheres, like man, exhibit facial abbreviation and cranial
elongation (postopie dolichocephaly) in contrast with the facial
elongation (prodpic dolichocephaly) of the horses. These phe-
nomena are similar to those of cytocephaly, or the bending
down of the face upon the base of the cranium as observed in
the reindeer (Rangifer) and the hartbeest (Bubalis). Cyto-
cephaly is an ontogenetic and phylogenetic new character, aris-
ing or developing continuously.

As in the case of the human skull, the causes of these pro-
found changes in head form are entirely unknown; the mechan-
ically adaptive significance is sometimes apparent, sometimes
obscure. By the examination of the titanotheres the evidence
is strengthened that human selection has little or no influence
on human eranial form.

The great point to emphasize is that this allometric evolu-
tion in the skull and all parts of the skeleton is the prevailing
phenomenon of change in the skeleton of mammals. It is con-
stantly in progress and is universally, so far as we can
observe, a continuous process. As displayed in the four phyla
of titanothere (Fig. 3), the elongations or broadening of the
foot bones proceed independently and are divergent, while in
the same mammals the rectigradations exhibited in the rise of

190 HARVEY SOCIETY
N.P.

Monophyletic ASS

Polyphyletic HORSE

Fig. 5. Cross-BREEDING AND IMPERFECT BLENDING oF ALLOMETRIC ‘‘ UNIT CHARAC-
TERS’’ oF THE FactaL Bones IN Ass (MALE), Horse (FEMALE) AND MULE.
Bones of the side of the face, Ass.
Bones of the side of the face, Mule.
Bones of the side of the face, Horse.
The horse is certainly polyphyletic, the ass is probably monophyletic. C. The arrow
points to C, a distinct bump in the horse and mule, not observed in the ass. S = point at
which the section of the nasalsistaken. L=lachrymal. N.P.=naso-premaxillary suture.

ORIGIN OF UNIT CHARACTERS 191

similar cusplets on the teeth and similar horn rudiments on the
face are convergent; in the former case no ancestral predis-
position seems to be operating, in the latter case ancestral
predisposition certainly seems to operate; this is why the in-
ternal laws controlling the origin of new allometrons and of
new rectigradations and allometrons are regarded as essentially
dissimilar.

Paleontological analysis of these rectigradations and
allometrons, even unaided by experimental heredity, reveals the
essential feature of the ‘‘unit character’’ principle, namely,
that what we are observing is an incredibly large number of
unit elements each of which enjoys a certain independence of
evolution at the same time that each unit is adaptively corre-
lated with all the others. For example, in the upper and
lower grinding teeth of horses alone there are 504 cusp units,
each of which has an independent origin and development; at
the same time each cusp is more or less distinctly correlated
in form with the all-pervading dolichocephaly or brachycephaly
of the skull; in fact, from certain single cusps of the teeth we
ean often determine whether the animal is brachycephalic or
dolichocephalie.

As a result of the somewhat conflicting evidence as to the
crossing of brachycephals and dolichocephals in man, the ques-
tion arises what happens when we cross two phyla of lower
mammals which have been diverging along separate allometric
lines and in the meantime have acquired a greater or less
number of new characters which when sufficiently developed
attain specific rank.

The answer is given very distinctly in the cross between the
dolichocephaliec horse (E£. caballus) and the mesocephalie ass
(E. asinus). Tere we learn again that profound differences
have been established through continuity and that we are
enabled to split up these differences into distinct or partially
blending units through eross breeding.

192 HARVEY SOCIETY

6. Blended or Alternating Heredity in Horses **

So high an authority as J. Cossar Ewart (1903) has sus-
tained the prevailing view that in the mule there is generally
an imperfect blending of the characters of the immediate
parents; the same author, however, notes that mules occa-
sionally serve as examples of unit or exclusive inheritance.*"
He cites two cases: (1) a mule out of a well-bred, flea-bitten
New Forest pony closely resembles her sire, the ass; (2) a
‘*calico’’ mule, on the other hand, is surprisingly. like his dam,
an Indian ‘‘painted’’ pony. This painted mule demonstrates
that the ass is not always more prepotent than the horse.
From this author’s very extensive breeding experiments the
following conclusions are reached: the less fixed or racially
valuable characters of zebras either blend with or are dominated
by the corresponding characters in their horse and ass mates.
Thus, as influencing dominance or prepotency, the value which
a character has attained in the past struggle for existence seems
to count for something. In zebras and in horses certain phy-
sical and mental traits are more highly heritable than others.
Among the characteristics which are often handed down un-
blended in zebra-horse hybrids and to a less extent in zebra-ass
hybrids are the size of the ears, the form of the hoofs, the
massiveness of the jaws; while among psychic characters are
transmitted the extreme caution, the wonderful alertness and
quickness.

The new results brought forward in this Harvey Lecture
from the comparison of the skull and teeth of the horse, ass

* The writer is indebted to Mr. S. H. Chubb, Mrs. Johanna Kroeber
Mosenthal, and to Dr. W. K. Gregory for many of the observations
and all of the measurements on which this comparison is based. The
materials studied are three skulls of the ass (¢ H. asinus), ten of the
horse ( Q E. caballus), and four of the mule, all adult with teeth in
approximately the same stage of wear.

“The most recent (1912) opinion of Ewart is much more positive
as to the operation of Mendel’s law in pure breeding strains of horses.
See Eugenics and the Breeding of Light Horses, The Field, February
10, 1912, pp. 288, 299.

ORIGIN OF UNIT CHARACTERS 193

Ss}

ASS

MULE

HORSE

Fia. 6. Cross-BREEDING AND ImppRFEct BLENDING OF SuB-aLLomMErRic ‘ UNIT
CHARACTERS” OF THE NasAL Bonus IN Ass (MALE) AND Horsp (FBMALB).

Top view of nasals and naso-frontal suture, Ass.

Top view of nasals and naso-frontal suture, Mule.

Top view of nasals and naso-frontal suture, Horse.
S=point of section shown in Figs. 3 and 5.

194 HARVEY SOCIETY

and mule on the whole strengthen the theory of unit inheritance
both in rectigradations and in allometrons. The measure of
unit character inheritance as contrasted with blended inher-
itance is very precisely brought out in the detailed study of the
twenty-two characters which are examined below. Before dis-
cussing these characters in detail it is interesting to point out
that the ancestors of the horse and the ass have probably been
separated for at least 500,000 years. In the meantime the
horse has become extremely dolichocephalic, the ass has re-
mained comparatively mesocephalic; the horse has a relatively
long, the ass a relatively short face; the horse has highly com-
plex, the ass has somewhat simpler grinding teeth; the horse
exhibits advanced adaptation to grazing habits and has be-
come habituated to a forest and plains hfe in comparatively
fertile countries, while the wild ass is by preference a browsing
animal, finding its food in excessively arid countries where
there is a marked dearth of water and water courses. The
physical and psychical divergences in these two animals have
developed over an enormously long period of time. Every
single tooth and bone of the horse and ass shows differences both
as to rectigradation and as to allometric evolution.

One feature which tends to make the results of the cross
less clear and distinctive than they are is that while the ass
is monophyletic (being descended with modification from the
wild E. asinus of northern Africa), the domestic horse is not
a pure strain and is certainly polyphyletic, having in its blood
that of several races, such as the Arab and the Forest or Norse
horse, animals which have specific distinctness although they
still interbreed.*® To this mixed strain or polyphyletic heredity
of the horse, are probably attributable in the mule many of the
allometric variations in the bones of the skull and in the enamel
pattern of the teeth in some of which we observe a nearer
approach to the ass type than in others. If we could cross the
ass with a pure horse race like the Steppe or Prjevalsky horse

“There are many absolute characters which separate the Arab
from the Norse horse, among them the invariable presence of one less
vertebra in the lumbar region of the back.

ORIGIN OF UNIT CHARACTERS 195
we should probably obtain more precise results. Another dis-

turbing feature in the comparisons and indices given below is
that we do not know the exact structure of the skull of either

Monophyletic

MA MULE

Polyphyletico

Fia. 7. Cross-BREEDING AND IMPERFECT SEPARATION OF ALLOMETRIC ‘‘SuB-
unir CHARACTERS’ OF THE NasaL Bones IN Ass (Matz), Horse (FEMALE)

AND MULE.
Mid-section of nasal bones, Ass.

Mid-scetion of nasal bones, Mule.
Mid-section of nasal bones, Horse.

Y1, Y2=variations in the depth of the nasals in the mule. V1,V?=variations in the
depth of the nasals in the horse.
of the parents from which the mule skulls examined were
derived.

Despite these sources of fluctuation and of error, the general
results obtained are fairly positive and definite.

196 HARVEY SOCIETY

The first point of interest as to the segregation of unit
characters in the mule is that connected with the three germinal
layers, namely, the epiblast, mesoblast and hypoblast.

All the characters of epiblastic origin appear to be derived
from the sire, namely, the epidermal derivatives, the distribu-
tion of the hair, especially in the mane and tail, the hoofs, ete.,
are those of the ass, although the color pattern, as in the
“‘ealico’’ mules described by Ewart, may be derived from the
mare. The nervous system and psychic tendencies, also of
epiblastic origin, are also derived from the ass, including minor
psychic characteristics, such as aversion to water. Still more
striking, perhaps, is the fact that the enamel pattern of the
grinding teeth, again of epiblastic origin, is mainly that of the
ass, although, as shown below, there are some intermediate
and some distinctive horse-like characters in the teeth of the
mule; this may be partly connected with the mesoblastic deriva-
tion of the dentine of the teeth.

Mesoblastic derivatives, on the other hand, are divided
between the sire and dam, the skeleton and limbs of the mule
being mainly proportioned as in the ass, while the skull of the
mule, as we shall see, is almost purely that of the horse.

Blending and Pure Inheritance in the Bones of the Face

Blending.—A comparison of the bones of the side of the
facial or preorbital region shows intermediate or partly blended
form and proportions both of the nasals, premazillaries,
frontals, and lachrymals, in which, however, the mule ap-
proaches E. caballus rather than E. asinus. Attention may
be called to some of the details of the comparison: (1) Suture
between the nasals and premazillaries: in E. asinus short and
elevated, in the mule intermediate but more lke the horse;
in the horse elongated and depressed (see Fig. 5). (2) Naso-
frontal suture on the top of the skull: in the ass straight or
transverse; in the mule inecurved, more like the horse than the
ass; in the horse arched or incurved (see Fig. 6). (3) Depth
and convexity of the nasals: in the ass shallow and flattened ;
in the mule deeper, more like the horse; in the horse highly

ORIGIN OF UNIT CHARACTERS 197

arched. (4) Bump or convexity on posterior third of nasals:
in the ass very slight; in the mule moderate, more like the horse
than the ass; in the horse strong (see Fig. 7).

The same tendency in the mule to exhibit a shght departure
from the horse toward the ass type is shown in the outlines
of the bones of the face (Figs. 3, 4, 5). Comparing step by
step the premaxillaries, maxillaries, nasals, and lachrymals,
while the proportions and the sutural outlines are mainly those
of the horse, there is a more or less distinct blending, or inter-
mediate character in the direction of the ass; see especially
the naso-premaxillary suture, and the degrees to which the
nasals extend on the sides of the face to join the maxillaries.
In this naso-maxillary junction certain horses approach the
ass type. The characteristic bump on top of the nasals of the
horse is transmitted to the mule, and the highly characteristic
transverse suture between the frontals and the nasals, as seen
from the top (Fig. 4), is rather that of the horse than of
the mule.

Non-blending indices——More definite results are shown in
the heredity of the indices or ratios between the various por-
tions of the skull and of the teeth; these indices are extremely
constant allometric specific characters, they are independent
of size. For example, the indices of a diminutive pony and of a
giant percheron would be the same. Similarly the indices of
a diminutive donkey and of a very large ass would be the
same.

The index is the best and most exact form of expressing
mathematically the profound differences between the skull of
the horse and that of the ass. Indices have the value of spe-
cific characters; they are of especial significance in the present
discussion in comparison with those in the face, cranium and
palate of man and of the titanotheres above considered.

Chief among the allometrie differences are the following:
(1) In its proportions the ass has a relatively shorter space
between its grinding and its eutting teeth, the bit-opening;
this is correlated with the fact (2) that the ass has a relatively
broader and shorter skull than the horse; also with (3) the

198 HARVEY SOCIETY

fact that the ass has a relatively longer cranium (postorbital
space) and shorter face (preorbital space) than the horse;
(5) the ass also has relatively broader grinding teeth corre-
lated with the broader skull; (6) correlated also with its less
elongate skull the ass has a relatively rounder orbit than the
horse, 7.e., the vertical and horizontal diameters are more
nearly equal. (7) A very distinctive feature is the angle
which the occiput makes with the skull; this is one of the
marked specific features of the ass.

Non-BLENDING OR PuRE INHERITANCE INDICES IN THE SKULL

Width of skull x 100 Ass 46.9— 49.9

1. Cephalic Index: a Mule 40.8- 43.6
Basilar length Horse 40.4— 44.1

Diastema X 100 Ass 15.6— 17.6

2. Diastema Index: Se Mule 18.6— 21.9
Basilar length of skull Horse 18.2— 23.0

Length of cranium x 100 Ass 656.3— 61.0

3. Cranio-facial Index: ————————————___ Mule 48.9- 51.8
Length of face Horse 45.3-— 49.9

Ass 96.0-104.2

4. Orbital Index:

Vertical diameter of orbit x 100

Horizontal diameter

Mule 78.7-— 99.1
Horse 84.2-— 93.5

Transverse diameter of M?X100 Ass 15.2— 16.0
5. Molar Index: Mule 14.2— 14.9
Total length of entire molar series Horse 13.9— 15.7
Angle between vertex of skulland Ass 52.5— 60.0
line connecting most posterior Mule 61.0— 66.5
6. Occiput-vertex points of hye crest with con- Horse 64.0— 76.5
angle Index: dyles, 7. e., nearly all horse skulls
will end: when set up on end,
some mule skulls (one out of four),
no ass skulls
Distance from palate to posterior Ass 93.8-111.7

7. Vomer Index:

end of vomer X100

Distance from vomer to foramen
magnum

Mule 95.5-110.3
Horse 72.8- 86.5

ORIGIN OF UNIT CHARACTERS 199

The above indices prove that the mule has not a primitive
skull like that of the ass on a larger scale, but has essentially
the skull of the horse, namely:

. A long, narrow skull, as a whole.

. A long diastema, or space for the bit.

. A short cranium and a long face.

. A long, oval orbit.

. A relatively elongate and narrow set of grinding teeth.
. A vertically placed occiput.

nore WD

The one character in which the mule resembles the ass is
the elongation of the vomer behind the bony palate. It should,
however, be distinctly stated that while the indices given above
are those which probably prevail in mules, there are overlaps
in the (4) orbital index and (6) occiput-vertex angle. Thus
in one mule the orbital index agrees with that of one of the
asses.

Enamel Pattern of Grinding Teeth—In the marvellously
complex pattern of the grinding teeth the ‘‘unit character’’
transmission is quite sharply defined in the majority of char-
acters, while intermediate or slightly blended in the minority.
In general in the grinding teeth of the ass the main enamel
folds are less complicated than in the horse and there are fewer
secondary or subsidiary folds; the ass especially lacks the
‘‘pli eaballin’’ (fold 5) which is usually a very pronounced
specific character of the horse. The mule shows a very slight
indication of this fold and thus resembles the ass. The sub-
sidiary folds in the grinders of the mule are simpler than those
in either the horse or the ass. The grinder of the mule would
be pronounced by any systematist not knowing its mixed
parentage to belong to the ass rather than to the horse, espe-
cially in the absence of the ‘‘ pli caballin ’’ (fold 5), in the form
of the hypostyle (hs, fold 6), in the smaller size of the proto-
eone (pr), the large size of which is very distinctive of the
horse, <A very detailed study and comparison of the grinding

200 HARVEY SOCIETY

folds: (1,3,4) ASS

folds: (1,2,3,4) MULE

folds: (1,2,3,4,5,6) HORSE

Fia. 8. Cross-BREEDING AND SEPARATION OF RectigRapations, Distinct “ Unit
CHARACTERS”? IN THE ENAMEL FoLpINGS AND PATTERN OF THE GRINDING TEETH OF
THE Ass, MuLE AND Horse. Section through the crown of the third superior grinder
(p‘ or 4th premolar) ass (male), horse (female) and mule.

ORIGIN OF UNIT CHARACTERS 201

teeth in the horse, ass and mule made by an independent ob-
server, Dr. W. K. Gregory, gives the following result:

Primary elements: protocone, pr.
paracone, pa.
metacone, me.
hypocone, hy.
protoconule, pl. Key to Figure 8.
metaconule, mil.
Secondary elements: parastyle, ps.
mesostyle, ms.
hypostyle, hs.

Secondary folds:
olde laa Horses. a Mule ee Ass
fold 2 Horse ei Mule
fOldaS lapse ilorse. see Miles: .i.72 Ass
fold) 2 ee Horse ..... Mule <3 5. Ass
fold@ bese Horse

Unit CHARACTERS IN GRINDING TooTH OF THE MULE
Distinctly ass-like: 5 characters .
Less distinctly ass-like: 6 characters \ 11 peculiar to ass.
Common to horse and ass: 5 characters 5 common to horse and ass.

Distinctly horse-like: 2 characters .
Less distinctly horse-like: 4 characters \ 6 peculiar to horse.

It would be especially desirable to compare the same enamel
characters in the hinny, which is a cross between the male
horse and the female ass, in which it is well known that the
E. caballus and E. asinus characters are differently distributed.

Summary.—Out of the 28 characters examined in the skull
and teeth of the mule, 18 are distinctly derived either from one
parent or the other with very slight, if any, tendency to blend,
while 10 characters show a distinct tendency to blend.

This evidence, in the opinion of T. H. Morgan, is in entire
accord with the modern views of hybridizing; parallels for each
instance can be given; without the evidence of the F, genera-
tion no conclusions adverse to Mendelism are possible. Even
the differences in reciprocal crosses, 7.e., horse ch’, ass 2, can
be understood if sex-limited inheritance prevails in some char-
acters.

To confirm the results suggested by this F, generation of
the horse and ass, it would be necessary to interbreed races of

202 HARVEY SOCIETY

mammals to F, or F, to ascertain whether these characters
of the skull and teeth really mendelize. It is doubtful whether
such specific types of mammals can be found, and whether
sufficient stability of character exists in artificially produced
races,

Sufficient evidence has been adduced, however, to show that
a very large number of characters which are to the best of our
knowledge of continuous origin present all the appearance
of ‘‘unit characters’’ in the first generation of hybrids.

Conclusions

Is it not demonstrated by this comparison of results obtained
in such widely different families as the Bovide, Hominide,
Titanotheriide and Equide that discontinuity in heredity
affords no evidence whatever of discontinuity of origin?

As to origin is it not demonstrated in paleontology that
certain new characters arise by excessively fine gradations which
appear to be continuous? If discontinuities or steps exist they
are so minute in these characters as to be indistinguishable
from those fluctuations around a mean which seem to ac-
company every stage in the evolution and ontogeny of unit
characters.

IIT. THEORETICAL CONSIDERATIONS

After having attempted to confine our lecture to opinions
and facts it is a pleasure to relax into the more genial att-
mosphere of speculation.

The principle of pre-determination, which results in the
appearance of rectigradations, involves us in radical opposition
to the opinions of the Bateson-DeVries-Johannsen school.
There is an unknown law operating in the genesis of many
new characters and entirely distinct from any form of indirect
law which would spring out of the selection of the lawful from
the lawless. This great wedge between the ‘‘law’’ and the
‘‘chanee’’ conception in the origin of new characters which
since the time of Aristotle has divided biologists into two schools
of opinion, is driven home by modern paleontology.

ORIGIN OF UNIT CHARACTERS 203

Paleontology, in the origin of certain new characters at
least, compels us to support the truly marvellous philosophic
opinion of Aristotle, namely:

Nature produces those things which, being continuously
moved by a certain principle contained in themselves, arrive at
a certain end.

While recent biology has tended to distinguish sharply
bodily from germinal processes and to place chief emphasis
upon evolution appearing to originate in the germ cells, we
must not forget that for a hundred million years or more, or
from the beginning of life, the germ plasm has had both its im-
mediate somatic and its more remote environmental influences.
Because the grosser form of Lamarckian interpretation of
transmission of acquired characters has apparently been dis-
proved, we must not exclude the possibility of the discovery of
finer, more subtle relations between the germ plasm and the
soma, as well as the external environment, There are several
phenomena, which have been observed only in paleontology,
that afford evidence for the existence of such a nexus; be-
cause it appears that certain germinal predispositions to the
formation of new characters, connected, as Darwin conjectured,
in some way with community of descent, are only evoked under
certain somatic and environmental conditions, without which
they appear to lie in a latent, potential or unexpressed form.

All that we ever may be able to observe are the modes of
operation in the genesis of new characters and in the adaptive
trends of allometric evolution without gaining any intimate
knowledge of what the causes are.

This thought may be made clear through the following anal-
ogy. Naturalists observed and measured the rise and fall of
the tides long before Newton discovered the law of gravitation;
we biologists are simply observing and measuring the rise and
fall of the greater currents of life. It is possible that a second
Darwin may discover a law underlying these phenomena bear-
ing the same relation to biology that the law of gravity has to
physics, or it is possible that such law may remain forever
undiscovered.

204. HARVEY SOCIETY

Another analogy may make our meaning still clearer.
Ontogenesis is inconceivable—for instance, the transformation
of an infinitesimal speck of fertilized matter into a gigantic
whale or dinosaur; we may watch every step in the process
of embryogeny and ontogeny without becoming any wiser; in
a similar sense phylogenesis may be inconceivable or beyond
the power of human discovery.

Not that we accept Driesch’s idea of an entelechy or
Bergson’s metaphysical projection of the organic world as an
individual, because we must believe that the entire secret of
evolution and adaptation is wrapped up in the interactions
of the four relations *° that we know of, namely, the germinal,
the bodily, the environmental, with selection operating in-
cessantly as the arbiter of fitness in the results produced.

In the meantime *° we paleontologists have made what
appears to be a substantial advance in finding ever more con-
vineing evidence of the operation of law rather than of chance
in the origin and development of new characters, something
which Darwin had in his prophetic mind.**

*® Four Factors, ete.

“ Osborn, H. F.: The Hereditary Mechanism and the Search for
the Unknown Factors of Evolution, Biol. Lect. Marine Biol. Lab.,
1894, Amer. Naturalist, vol. xxxix, No. 341, May, 1895, pp. 418-439.

“Darwin, Chas.: “I have spoken of variations sometimes as if
they were due to chance. This is a wholly incorrect expression; it
merely serves to acknowledge plainly our ignorance of the cause of
each particular variation.”

THE RELATION OF MODERN CHEMISTRY
TO MEDICINE*

PROF. THEODORE WILLIAM RICHARDS
Harvard University

OUR centuries ago, in the days of Paracelsus, chemistry
was ¢alled ‘‘ the handmaid of medicine,’’ and the chief
office of the immature science was to serve the art of healing
by the preparation of drugs. If her service was often of
doubtful value, the defect lay not so much in the lack of
latent possibilities as in their exceedingly inadequate develop-
ment. To-day, opportunities of usefulness for the still youth-
ful science in the service of the ancient art are immeasurably
widened. Not only in the mere preparation of drugs, but in
countless deeper and farther-reaching ways, are the two
branches of learning united in a common cause. Indeed, it
is no exaggeration to say that chemistry holds the key which
alone can unlock the gate to really fundamental knowledge of
the hidden causes of health and disease. This is one of the
most precious and vital ways in which any branch of science
can serve humanity in the years to come.

The lecture to-night is designed to present a brief logical
summary of the more important relations of chemistry to
those parts of biology especially pertaining to medicine, as
viewed from the stand-point of the theoretical chemist. Not
only the present state of these relations, but also their prob-
able development in the near future, will be briefly indicated,
In thus especially emphasizing the chemical side of life, I do
not wish to detract from the likewise essential messages of the

* Delivered February 3, 1912. This lecture is an amplification of

a brief address delivered on the occasion of the seventy-fifth anni-
versary of Haverford College, and published in the “ Atlantic
Monthly ” for January, 1909.
' 205

206 HARVEY SOCIETY

physiologist, anatomist, pathologist, bacteriologist, and psy-
chologist. All must work together towards a common end.

That a close relationship between chemistry and medicine
exists is clear to every one. Our bodies are wholly built up
of chemical substances, and all the manifold functions of the
living organism depend in great measure upon chemical re-
actions. Chemical processes enable us to digest our food, keep
us warm, and supply us with muscular energy. It is highly
probable that even the impressions of our senses and the
thoughts of our brains, as well as the mode of conveying these
through the nerves, are all concerned more or less intimately
with chemical reactions. In short, the human body is a won-
derfully intricate chemical machine; and its health and ill-
ness, its life and death, are essentially connected with the co-
ordination of a variety of complex chemical changes.

Why, then, if this relation of chemistry to medicine is so
obvious, has chemistry only so very recently been able to
render medicine any signal service? The answer is manifest.
The intricacy of the living body demands clear sight and pro-
found knowledge for its full understanding; and the chem-
istry of former days was much too simple and superficial to
be a very useful guide in the puzzling labyrinth of many
converging and crossing paths. Now, circumstances have
greatly changed, and bid fair to change yet more in the near
future. Chemistry is fast approaching physics in accuracy,
and is expanding beyond physics in scope. As chemical
knowledge has increased, the gap between the simpler phe-
nomena of the chemical laboratory and the more complicated
changes. underlying organic life has become smaller and
smaller. The intelligent physician, perceiving this, welcomes
the help which the rapidly advancing science of chemistry can
give him. Both physiologist and pathologist in the study of
the cell and its normal or abnormal growth must ultimately
Yall back upon chemical knowledge, because the action of the
cell depends essentially upon the nature and quantity of the
various chemical substances of which it is made. As the cell

RELATION OF CHEMISTRY TO MEDICINE 207

is the basis of all life, and as our bodies consist simply of aggre-
gations of a great variety of cells, each of which is governed
by chemical laws, chemistry must underlie all the vital fune-
tions.

Chemistry may be of use to medicine in at least three quite
different ways besides the practical preparation of the sub-
stances described in the Pharmacopeia. One of these is con-
cerned with ascertaining the composition of all the substances
pertaining to organic life. This kind of chemistry is, as you
know, called analytical chemistry. Another way in which
chemistry can help medicine depends upon the ability of the
modern chemist not only to discover the elements present,
but also to find how the parts are put together. This branch
of chemistry is called structural chemistry, because it has to
do not only with the materials but also with the way in which
these materials are arranged. Yet another method of help-
fulness comes from a still more recent development of chem-
istry, commonly ealled physical chemistry, which deals with
the relation of energy to chemical change. The physical chem-
ist must know not only the composition and structure of the
substances, but also what kind and quantity of energy is con-
cerned in putting them together, and how this is set free when
they are decomposed. He deals with chemical change in ac-
tion, and studies its method of working.

Each of these three kinds of chemistry can greatly aid
the science and art of medicine—and no philosopher is needed
to predict how much more effective their assistance may be
than the old method of observing merely the outward appear-
ance of fluid and tissue.

Let us now briefly glance in detail at the various aspects
of these three modes of helpfulness, taking them in the order
in which they have just been mentioned. First comes the
field of the analytical chemist. As has been said, the human
body is a chemical machine. It is composed entirely of
**chemicals,’’ and is actuated exclusively by chemical energy.
The analytical chemist is able to tell us the composition of each

208 HARVEY SOCIETY

one of the manifold substances that compose this intricate
machine. He tells us that much of the body consists merely
of the simplest compound of oxygen and hydrogen, namely,
water; that fat is a more complex compound containing the
same two elements with the addition of carbon; that the pro-
teins of muscle contain nitrogen, that the nerves and bones
contain phosphorus, and so forth. He is able not only to
discover the various elements which are present, but also to
estimate with considerable precision their exact amounts.
Moreover, he can often isolate the various compounds of these
elements which may be mixed together in any given tissue.
These facts are not only the essential basis for the intelligent
development of the structural and physical chemistry of the
body, but they also have immediate practical applications of
great importance. The analytical chemist can analyze food
and drink, as well as the various parts and secretions of the
body, and can determine the relation between the composition
of that which is eaten and the resulting bodily substance. This
is obviously of great value, for it shows us at once in a general
way what substances ought to enter into our diet, and more-
over, in cases of disease, it gives us excellent clues to the man-
ner in which the various functions of the body depart from
the normal, and thus confers important aid in diagnosis and
prognosis and the suggestion of suitable treatment. Analyses
of the secretions of the kidney and the stomach have long been
used in this way. Another quite different office—the detection
of poisons—is a matter of great importance in medicine as
well as in criminal law.

All these relations of chemical analysis to the art of heal-
ing are well known to most intelligent people, hence I will not
dwell further upon the analytical side of the application of
chemistry to medicine, important as it is.

Let us now turn to the second aspect of the subject, namely,
the relation of structural chemistry to medicine. So recent is
the development of the subject that the very idea of struc-
tural chemistry is not yet a part of the average liberally edu-
cated man’s equipment.

RELATION OF CHEMISTRY TO MEDICINE 209

Structural chemistry had its origin in the discovery that
two substances might be made up of exactly the same percent-
age amounts of exactly the same elements, and yet be entirely
different from one another. This fact, that two things may
be exactly alike as to their constituents, but very different in
their properties, implies that there must be a difference of
arrangement of some kind or other. We can obtain the clear-
est conception of this idea with the help of the atomic hy-
pothesis. If the smallest particles of any given compound
substance are built up of still smaller atoms of the various
elements concerned, it is clear that we can conceive of different
arrangements of these atoms, and it is reasonable to suppose
that the particular arrangements might make considerable
difference in the nature of the resulting compounds. Every-
where in life arrangement is significant. In spelling even sim-
ple words, different arrangements of letters cause wholly differ-
ent effects, as for example in ‘‘ art ’’ and ‘“‘ rat’’; and count-
less other cases might be cited. Why may not arrangement
be significant in the case of atoms?

It is not possible in this brief address to explain exactly
how chemists obtain a notion of the arrangement of atoms
which build up the particles (or molecules) of each substance.
We depend upon two methods of working, one the splitting
up of the compound and finding into what groups it decom-
poses, the other, the building up from these or similar groups
the original compound. Just as among the fragments of a
collapsed building you will find bits enough to show whether
it was a dwelling, a stable, or a machine shop, so among the
fragments of a broken-down substance you will find bits of
its structure still remaining together, enough to indicate some-
thing of the original grouping. Each different chemical
structure will leave a different kind of chemical débris. If
from similar fragments the original substance can be recon-
structed by suitable means, the evidence is strong that some
knowledge of the structure has been gained. Albrecht Kossel
in his recent Harvey Lecture doubtless dwelt at length upon

210 HARVEY SOCIETY

this matter, but a moment’s recapitulation and a few concrete
cases may not be out of place. ;

For example, two well-known substances, ammonium
cyanate and urea, have each the formula CH,ON,. That is
to say, since each letter stands for a definite quantity of each
element, these two compounds are absolutely identical in com-
position. Nevertheless, the merest beginner, who takes the
two substances into his hands, can see that they themselves
are entirely different from one another in their appearance
and behavior. By heating the first substance in solution in
water it may be converted into the second, without any loss
or gain of material. The only way in which we can expiain
the likeness of compesition is by supposing that the atoms,
alike in numbers in each ease, are arranged differently; and
long study has led to the conclusion that the two arrangements
are best expressed by the following diagrams:

H H Tet Tél
H NOCN and NCN
H HOH

The second, more symmetrical arrangement, urea, is the
stabler of the two. That these two different arrangements
should cause different properties is not surprising.

Let me cite yet another case among the countless instances
which might be brought forward. Milk sugar and cane sugar
are unquestionably different in their physiological action, as
every physician knows. The difference, while unimportant to
most adults, is a very serious one for infants. Now these two
substances have exactly the same formula, C,.H,,0,,; in other
words, each molecule of each sugar is composed of 12 atoms
of carbon, 22 atoms of hydrogen, and 11 atoms of oxygen;
or 42.1 per cent. of carbon, the remainder being oxygen and
hydrogen in the same proportion as in water. Both, unques-
tionably different from one another, are evidently very differ-
ent from a mixture of charcoal and water possessing the same
percentage composition. These differences are ascribed, as
before, to differences in arrangement of the atoms, the case

RELATION OF CHEMISTRY TO MEDICINE 211

being analogous to that of ammonium cyanate and urea, just
cited. The detailed unravelling of the structure of the sugars
seemed until recently to be almost impossible, because the
number of possible combinations to be obtained from 45 atoms
in one molecule is so great. Nevertheless, this problem has
been almost if not quite solved by Emil Fischer, and we are
now able to say with some confidence wherein the differences
lie. The arrangements depicted in the two accompanying dia-
grams due to Fischer, probably come very near the relative
structures of the two substances.

H.COH ists
HCOH Dee
HEN HON
haeraS RS
leans ie ‘a
HCOH / HCOH /
ae Wa
HCC ACC
O O
7a de
ny EC
HOH:C-C |
He HCOH
Ne |
ica a pane
HCOH / pee
HC/ iia
H,COH HCO
Cane Sugar Milk Sugar

These formule, being depicted upon a flat surface, cannot
represent exactly the true arrangement of the atoms in space,
where the molecules oceupy three dimensions instead of only
two. The tridimensional distribution of atoms is a subject
of much importance, and since 1874 has grown into a special
branch of chemistry, called stereochemistry. No attempt is
made in the above formule to represent even by the usual con-
ventional arrangement the supposed space-configuration of the

212 HARVEY SOCIETY

atoms of either kind of sugar, because the most recent inves-
tigations seem to indicate that this matter is not finally set-
tled; but even without taking differences of this kind into
consideration, a glance is enough to show that the lower halves
of the two arrangements are not alike; and the difference is
enough to account for the difference in the physiological action
of the two sugars.

I cannot emphasize too strongly the fact that such differ-
ent groupings are not a mere question of mixture in the or-
dinary sense. No possible fashion of mixing together 42.1
grams of charcoal and 57.9 grams of water will produce 100
grams of any kind of sugar. The matter is far subtler than
this. It is a question of arranging almost inconceivably mi-
nute atoms within a molecule almost as small. That human
beings may thus imagine the relations which they cannot see,
devise a nomenclature for expressing these invisible relations,
and then pursue their quest even into prophesying unknown
relations which can be and very often have been verified by the
actual preparation of definite substances, seems to me one of
the most remarkable outcomes of the human imagination.

As regards the usefulness of structural chemistry to medi-
cine, we cannot but see at once its vast importance. If the
binding together of infinitesimal atoms in different ways pro-
duces different properties in the resulting substances, it is ob-
vious that the particular mode of binding together every one
of the complicated compounds constituting our bodies is of
vital importance to us. As the substances in the body usually
have many atoms in each of their molecules, there are a great
many different ways in which the atoms may be arranged;
and each one of these many arrangements may have different
effects. Among the many substances now under investiga-
tion of this sort, the proteins or albuminous substances stand
out prominently, for they play so essential a part in the
animal mechanism. The recent synthesis by Emil Fischer of
complex amino-acids into protein-like compounds points the
way towards a better chemical understanding of these highly

RELATION OF CHEMISTRY TO MEDICINE 213

important bodies, and this knowledge will doubtless be the
stepping-stone to more. The work of Willstitter concerning
the structure of hemoglobin is also of great importance to
physiology.

Living, in the case of all animals, is a continual process of
breaking down more complicated structures into simpler ones;
and it is clear that this breaking down will happen in different
ways with different groupings, and thus produce different re-
sults. In the case of food, the arrangement alone of the atoms
may make all the difference between nourishment and poison.

The knowledge of the atomic arrangement of the various
substances composing the body is not only bound to furnish
an invaluable guide in the study of physiology, pathology, and
hygiene, but has already led to the logical discovery of en-
tirely new medicines, built up artificially in the laboratory to
fit the especial needs of particular ailments. Examples of
this sort will occur to every physician. The narcotic, veronal,
was deliberately sought by Emil Fischer, who based his re-
search upon the known physiological action of sulphonal and
other similar substances. He sought to put into the molecule
the groups which were effective in diminishing nervous activity
and to take out of the molecule such groups as had been proved
to have depressing action on the heart. Again, the newer and
still more astonishing substance, salvarsan, of Ehrlich, was
the result of an extended experimental search in which succes-
sive groups were attached to the arsenic nucleus until its viru-
lent action on the human organism was sufficiently diminished,
without essentially overcoming its destructive effect on the
germs of the loathsome contagion which it was designed to
destroy.

We all appreciate the profound revolution in medicine pro-
duced by serum treatment, and rejoice in its high promise.
Here in New York especially, epoch-making work along this
line has been accomplished by Dr. Flexner and his able assis-
tants in the already famous Rockefeller Institute for Medical
Research. But cannot pure chemistry in the future bring a

214 HARVEY SOCIETY

most helpful improvement into this noble work? At present,
various serums are prepared in the hidden laboratory of living
tissues; there is no other way. Nevertheless these serums work
unquestionably through the agency of chemical substances,
which very probably may be capable of production in a chemi-
cal laboratory, provided that their true nature can be dis-
covered. Thus could be manufactured antitoxins uncontami-
nated with other substances of doubtful value and possibly
deleterious effect; and the antitoxin treatment would lose
its most grievous handicap. Jn the future the physician may
do his work, not with a serum or virus of doubtful composi-
tion and value, but rather with pure substances built up in
the chemical laboratory—substances with their groups of atoms
so arranged by subtle science as to accomplish the reconstruc-
tion of worn-out organs or the destruction of malignant germs
without working harm of any kind. We may thus dream of
the attainment of an artificial immunity from smallpox, for
example, as much superior to vaccination as this is superior to
the old inoculation. That the whole subject of immunity,
already explained by a somewhat vague chemical hypothesis,
will lose its uncertainty and steadily gain in clearness as
chemical knowledge advances, no one can doubt.

The true chemical nature of the antitoxins and the real
nature of the chemical changes which establish immunity will
not be discovered by accident, however; the complexity of the
compounds and circumstances concerned is far too great.
Clearly, in order to know all there is to be known about the
matter, the structure of each intricate substance existing in
the body must be found, and the arrangement of the atoms in
each particle of our complex organism. Until this shall be
done, we cannot be in a position to predict with any reason-
able certainty what is going to happen to these substances
in the round of their daily functions, or how they are likely
to be influenced by disease. This is a problem so vitally im-
portant that it would be hard to exaggerate its significance to
posterity.

RELATION OF CHEMISTRY TO MEDICINE 215

Such researches will be of enormous value not only to cura-
tive medicine, but also to preventive medicine and the hygiene
of every-day life. If we know the structure of the proteins
in food and the way in which they react in the body, we shall
be able to choose intelligently the proper balance between the
different foods, towards which we are now groping rather
blindly. As it is, for all we know, a ‘‘nitrogen balance’’
between intake and outgo may be established in the body, the
bodily weight remaining constant, while some very important
substance is wasting away for lack of the particular groups
which are capable of replenishing its store. To obviate such
a catastrophe we need to know not only that a given food con-
tains so much nitrogen; we must know also how the nitrogen
is combined, for this latter fact makes a vital difference. Grove
and Hopkins’s work alone is enough to prove this. The ad-
mirable research of Osborne and Mendel upon the physiological
effect of pure proteins will doubtless throw much light on these
questions. Moreover, there are other elements, such as iron
in the essential red coloring matter of blood, and phosphorus
in nerves, where also the special form of combination is of
vital importance. Chemistry has gone far enough to see where
the problem lies, but not quite far enough yet to solve it. Such
a prospect is especially inviting to the investigator; he feels
confidence that he is reaching after truths within the mental
grasp of man, and therefore that he may rightfully hope to
succeed.

Let me emphasize once more the fact that these are essen-
tially chemical problems, to be solved in chemical laboratories
in the same way that Fischer unravelled the constitution of
the sugars; and upon work of this kind the medicine and hy-
giene of the future must be dependent to an extent not at all
realized by most physicians to-day. The progress of both cura-
tive and preventive medicine will be grievously handicapped if
chemistry is not permitted and encouraged to advance; only
a short-sighted community will put all its energy into the com-
paratively superficial observation of complicated outward phe-

216 HARVEY SOCIETY

nomena of life, without stimulating also the thoughtful study
of the fundamental chemical changes upon which everything
depends.

As I have said, the complete chemist must now know not
only what things are made of and how the elements are put
together, but also what forms of energy are concerned in
putting them together, and how much energy is set free when
they are decomposed. This applies to the biological chemist,
as well as to the theoretical and technical chemist.

There is no doubt that energy is the immediate cause of
every event in the known universe. Several well-known kinds
of energy exist; the chief forms are mechanical energy, heat,
light, electrical energy, and chemical energy. Each is capable
of transformation into each other form, and so far as we can
tell the sum total of the energy in the universe can neither
wax nor wane. Without any kind of energy, the whole uni-
verse would be chaotic, quiescent, dark, piercingly cold, asleep.
We can conceive, on the other hand, of a world possessing the
so-called physical forms of energy without chemical affinity.
What would it be like? Such a world, composed of elements
like argon, might revolve and have light and warmth, sea and
rocks, clouds, rain and tides; but it could possess no organic
life, for life is based upon the action of chemical energy. Thus
the study of chemical energy is of profound importance to the
student of organic life.

As has been said, the branch of chemistry which treats of
energy is called physical chemistry; it deals with the acting,
driving forces which make life possible, and in each of its many
aspects it brings new intelligence to bear upon the working of
the living mechanism.

Physical chemistry treats, among other topics, the chemical
relations of the changes from solid to liquid, and from liquid
to gas, and discusses the nature and behavior of solutions and
mixtures of all kinds. As the living body is composed of solids
and liquids and depends upon the gases of the atmosphere for
promotion of the chemical changes animating it, and as solu-

RELATION OF CHEMISTRY TO MEDICINE 217

tions and mixtures are present in every cell, the laws and
theories of physical chemistry are intertwined with every fact
of physiology.

Among the discoveries in these directions, none is of more
immediate importance to physiology and pathology than the
outcome of recent study of the behavior of liquids in relation
to partly permeable or porous ecell-walls of partitions. The
behavior is obviously capable of throwing light on the nature
of both liquids and porous partitions, and is of peculiar im-
portance in the animal economy, because most physiological
action has to do with liquids and cell-walls.

As the minute openings in a porous wall between two liquids
are made finer and finer, at first fine powders are unable to
penetrate, then bacteria are caught on the surface; then, as
the holes are made yet smaller, some of the dissolved sub-
stances, such as gelatin, are refused transmission; and at last
with the most finely porous wall, nothing but pure water goes
through. Even a solution of common salt, for example, be-
comes entirely sweet and fresh upon being pressed through
such a semipermeable membrane; it has been freed from the
almost infinitesimal particles of dissolved salt im somewhat
the same way that a jelly is freed from fruit seeds by strain-
ing or filtering through cloth, or water has been freed from
bacteria by a Pasteur filter. The work of Bechhold with the
ultrafilter and of Zsigmondy with the ultramicroscope have
especially demonstrated even to the layman this difference in
the size of dissolved particles, first discovered by Graham long
ago. Ag regards the mechanism of the penetration of solvents
through diaphragms, we may distinguish two classes of action—
the first class depending merely upon transmission through
holes, the size of which determines the separation of dissolved
substance, and the other class depending upon the true dis-
solving (to form a so-called ‘‘ solid solution ’’) of the sol-
vent in the material of the dividing wall on one side, and its
escape from this ‘‘ solid solution ’’ on the other.

One highly important feature of the action of a semiper-

218 HARVEY SOCIETY

meable diaphragm is the same, no matter which cause deter-
mines the mechanism of its action. So far as we can tell, each
separate dissolved particle, restrained from passing through,
exerts a certain definite pressure upon the dividing wall—a
pressure which Pfeffer first measured and which van’t Hoff
showed to be in dilute solutions essentially equal to that ex-
erted by any molecule at the same temperature in a gaseous
condition, and not dependent upon the nature of the dissolved
substance or of the solvent. The resulting effect, which thus
depends upon the number of the dissolved particles in a given
space, and not upon their character, is called osmotic pressure,
and may be actually measured. To give an idea of the mag-
nitude of these effects, it is enough to state that the osmotic
pressure of the blood of mammals is over one hundred pounds
to the square inch, or enough to support a column of water
nearly two hundred and forty feet high. Even the novice
must perceive the enormous significance of such conditions.

With the help of these and other allied phenomena, the
study of aqueous solutions has enabled us to discriminate be-
tween the various sizes and conditions of the smallest particles
of different dissolved substances. We find that some sub-
stances act as if their molecules split up into their so-called
ions, when dissolved, and these ions behave as if they were
electrically charged; this is the outcome of the theory of van’t
Hoff and Arrhenius. Other substances split up in another way,
ealled hydrolysis, combining with some of the water, and yield-
ing often a weak acid and base as the result of their decompo-
sition. Yet others apparently dissolve unchanged; and among
them some, called colloids, act as if they had very large mole-
cules, almost like very fine particles of a powder suspended in
the solution, or the fine drops of an emulsion.

It is clear that each of these different types of solutions
might be expected to act differently with regard to the walls
of the living cells which contain them. Some will penetrate
freely, perhaps; in others the dissolved molecules will be de-
nied entrance or exit, because of their mere size; in yet others

RELATION OF CHEMISTRY TO MEDICINE 219

the chemical nature of the individual particles will have pe-
euliar relations to the substance of the cell-walls, thus permit-
ting selective transmission and absorption in special fashion.
Probably the secretion of most animal fluids involves the com-
bined action of all these effects; and so does permeability of
the cell to outside mixtures, such as the blood plasma or any
given antitoxin.t

Profound insight as well as careful experiment will doubt-
less be necessary to unravel the tangled result. Nevertheless,
armed with a knowledge of the nature of solutions, the biolo-
gist may hope to conquer; without it, he must inevitably be
defeated. The study has already made good progress in at-
tacking the outposts; one may cite for example the highly
interesting and important work of J. Loeb upon the artificial
fertilization of some of the lower forms of animals, and that
of Henderson on the neutrality of the blood; here the physico-
chemical facts are seen to bear on some of the most funda-
mental and mysterious of the biologist’s problems. Indeed, as
Hamburger has recently said, ‘‘Quite inestimable has been
the influence exerted by the theory of solutions on our science.
There is hardly a chapter in physiology which does not bear
signs of this influence.’

The very large dissolved molecules of the colloids (or glue-
like substances) have peculiar properties, which are so im-
portant as to have given rise to a special branch of chemistry
ealled ‘‘ colloid-chemistry.’’ Colloids are plentiful in the hu-
man body; and every fact concerning their behavior is of the
greatest value in interpreting the many complex changes in
which they take part. One of their remarkable characteris-
tics, for example, is their power of clinging to substances in
contact with them; the large surface exposed by their extended
and diversified molecules seems to be especially able to hold
with a sort of adhesive attraction called ‘‘ adsorption ’’ not

*See Flexner, Biological Basis of Specifie Therapy, Ether Day
Address, Massachusetts General Hospital, 1911.
* Science, Nov. 3, 1911.

220 HARVEY SOCIETY

only large quantities of water, but also salts and everything
else within reach.

Another highly important aspect of physical chemistry is
that which concerns the speed of chemical reactions, and the
mechanism by which this speed gradually decreases in a given
mixture until a balancing or equilibrium of all the reacting
tendencies is attained. The speed of the chemical changes in
the human body is a matter of capital importance to man. In-
deed, it may be said that the difference between health and
disease, between life and death, is primarily a question of the
relative speeds of the various reactions concerned in the act
of living. There is fortunately a wide margin of safety, but
nevertheless if any one of the more essential chemical changes
takes place too fast or too slowly, illness is a certain conse-
quence.

All chemical reactions are dependent for their speed upon
a few very definite circumstances, to wit: the special affinities
of the substances concerned, the concentration of the reacting
substances, the temperature of the mixtures, and the presence
or absence of certain other substances (called catalyzers or
catalysts) which do not themselves take part, but which stimu-
late the reacting substances to enter into combination. Each
of these factors in the result is of great importance to the biolo-
gist. The effect of concentration is especially interesting; it
influences all the various kinds of reactions, whether between
a liquid and a solid, between a liquid and a gas, or between
several substances, dissolved in a single liquid. Whenever to
a nearly balanced mixture more of any reacting substance is
added, it tends to push faster and farther all the changes
in which it takes part, so that some of the added sub-
stance is used up. For example, if more water is added, all
the reactions which tend to use up or absorb water are acceler-
ated, and so forth. This is a very general law, which is sus-
ceptible of mathematical expression in each separate case; and
so is the somewhat analogous fact that increase of tempera-

RELATION OF CHEMISTRY TO MEDICINE 221

ture, which accelerates all reactions, especially furthers those
tending to absorb heat.

Again, the fourth cause affecting the speed of reactions,
namely, the action of catalysts, underlies many of our vital
processes. A class of catalysts, known as enzymes, the be-
havior of which has only recently been carefully studied, have
been shown to be of fundamental importance in the animal
economy, for they influence the essential progress of digestion
and assimilation, as well as many other vital functions.

The development of the heat and muscular energy of the
body by the slow combustion of its substances presents another
set of chemical effects without which life would be impossible.
The chemical mechanism of these changes is being investigated
by Dakin, who has been prosecuting his work in the inspiring
atmosphere of the laboratory of the late Christian Herter.
Dakin has found much of interest concerning the way in which
this combustion occurs at the comparatively low temperature
of the body, and his researches throw light on the manner in
which the complex substances constituting the body yield
energy by breaking up into the simpler products, eliminated
from the body through the lungs, skin, and kidneys. The re-
cent work of Rubner and of Atwater and Benedict has shown
that the conservation of energy applies to this burning just
as much as to the reactions in our beakers and test-tubes; the
marvellously complex living organism is not beyond the do-
main of this simple and fundamental law.

The dynamic chemistry of the future does not stop here,
however. Within its province lie also the recently found re-
lations of chemistry and electricity, bearing perhaps upon
some of the partly chemical and partly physical mysteries of
nervous action, and furnishing much intelligence concerning
the nature of solutions in general. The new science of radio-
activity, too, is a part of physical chemistry. The sterilizing
action of the X-rays and radium rays and emanations on the
germs both of life and of disease have highly important bear-
ings upon medicine. More significant perhaps than all this,

222 HARVEY SOCIETY

because more general, is the branch of physical chemistry
called photochemistry—the chemistry of light—which promises
to give great assistance in the interpretation of the changes
occurring in the leaves of plants under the influence of sun-
light. Through the agency of lght alone nature is able to
build up the intricate compounds needed to provide all ani-
mals with food; and until we understand the growth of the
vegetable we cannot hope to understand that of the animal.
Moreover, the photochemical analogies and differences between
the green coloring matter of plants and red coloring matter
of blood are full of suggestiveness; and the peculiar relations
of many natural substances to polarized light furnish a fund
of data for deep thought, not only concerning the arrangement
of the atoms in space, but also concerning the nature of life.
That the sense of sight depends upon photochemical reactions
in the retina, analogous perhaps to those which occur in sen-
sitized films prepared artificially, one can hardly doubt; thus
photochemistry may perhaps some day throw light on other-
wise hopeless forms of disease of the eye, as well as upon the
normal working of that highly important organ.

Indeed no aspect of physical chemistry which has to do
with the effect of energy upon material is too remote from
every-day life to be valuable, for everything which throws light
upon the nature of matter is a help in the interpretation
of the action of the substances composing our bodies. For
example, the recent theory which suggests that the atoms
themselves are compressible may bear fruit not now easily pre-
dicted, because this theory has to do with some of the ultimate
and most fundamental of the properties of all substances.*

In brief, the chemistry of energy promises incalculable
helpfulness to future generations of mankind. From the study
of inert substance from which life has departed, we cannot
infer certainly its real office, any more than we ean predict
from the appearance of a stuffed bird in a museum its com-
plete habit of life. In order to understand the process of liv-

RELATION OF CHEMISTRY TO MEDICINE 223

ing, one must study each substance in action, and examine its
behavior under the influence of the manifold forces which play
around it; and this is the aim of physical chemistry.

I have outlined very briefly a few of the ways in which
chemistry holds out great promise of help to suffering hu-
manity in the future. A few decades ago Pasteur and Lister
revolutionized the science of medicine and made a greater
advance than had been made in a thousand years before. One
of the great tasks of the future is to discover the ultimate
chemical reasons which underlie not only the mechanism of
bacterial action but also those upon which life itself is based.

What indeed is life? Is it nothing but a bundle of chemi-
cal reactions? From dead material alone man as yet has been
unable to create the simplest living cell, and yet these cells
seem to be entirely chemical in their action. Wherein lies the
explanation of the paradox? As Cuvier pointed out long ago,
life seems to be a directive tendency rather than a form of
energy. In a living organism actuated by chemical reactions,
using in accordance with definite laws the energy of the sun
while it runs down from a higher to a lower potential through
a complicated chemical mechanism, life directs the simulta-
neous processes in such a way that the body grows and flour-
ishes. How this is accomplished no man knows; but if the
mystery is ever explained, the explanation cannot ignore the
chemical changes which are bound up with every step. Even
psychology must take chemistry into account in its ultimate
reckoning; for are not our thoughts and nervous impulses in-
extricably associated with chemical changes in the nervous tis-
sue, and must not memory be due to permanent alterations
of chemical structure? Perhaps heredity, too—that most re-
cent concern of biologist and psychologist alike—may be found,
as has been repeatedly suggested, to depend in the last analy-
sis upon the existence of definite chemical substances—possi-
bly special catalysts—in the several chromosomes carrying on
the process of reproduction, by which we now explain Men-
del’s law.

224 HARVEY SOCIETY

The outlook for the future is thrilling in its possibilities.
Nevertheless, as du Bois Raymond insisted, we can never hope
to understand the whole of the wonderful secret. We are here
living in a small restricted world with an infinity of space on
all sides of us; we crowd our little deeds into a relatively in-
finitesimal limit of time, with eternity beyond us and in front;
and both infinity and eternity are beyond the grasp of our
finite minds. But let us not be impatient. Even if a com-
plete understanding of the secret of life and death is unat-
tainable, step by step we shall gain in knowledge. Each ad-
vance furnishes new vantage ground for further progress and
new inspiration for fresh effort; and with our steadily increas-
ing knowledge grows our ability to help suffermg humanity
and to strengthen coming generations. Thus we may look for-
ward with high hope toward the undiscovered future.

SOME CURRENT VIEWS REGARDING THE
NUTRITION OF MAN*

PROF. RUSSELL H. CHITTENDEN
Sheffield Scientific School of Yale University

O all who are truly interested in the development of

knowledge, information counts for more than argument,
truth for more than tradition; facts weigh more than opinions.
Controversial argument sometimes makes interesting reading,
but it rarely convinces unless based upon a foundation of fact
that will in itself convince. In what I have to say this evening
I shall try to avoid so far as possible controversial statements
and arguments, emphasizing rather those views that seem
warranted by the facts at our disposal.

The modern conception of nutrition finds its beginning in
the discoveries of Lavoisier, who made clear the important part
played by oxygen in the two processes of combustion and
respiration. He soon came to see that the processes of life
are essentially processes of oxidation, in which carbon dioxide
is a conspicuous waste product while heat is another resultant,
proportional in amount to the degree of combustion or oxida-
tion. Lavoisier, though working with apparatus and methods
far less refined than those at our disposal to-day, quickly
determined that man takes in oxygen and gives off carbon
dioxide in amounts which vary with the quantity of food con-
sumed, the amount of work done, and the temperature of the
surrounding air. At first, it was conjectured that the oxidation
oceurring within the body took place in the lungs or in the
blood, and that it was carbon and hydrogen that underwent
combustion. The work of Liebig, however, eventually made

* Delivered February 17, 1912.

226 HARVEY SOCIETY

it quite clear that the substances undergoing oxidation in the
body were the proteins, fats, and carbohydrates of the food and
tissues, and further, that while carbon dioxide was a measure
of the amount of carbonaceous matter burned up, the nitrogen
eliminated constituted a measure of the amount of protein or
nitrogenous matter broken down. This view, which was
advanced by Liebig about 1842, was confirmed and strength-
ened by the experimental work of Bidder and Schmidt and of
Carl Voit during the period from 1850 to 1860. Moreover,
it became apparent that the processes of oxidation were not
limited to any one place, to any one tissue or organ, but were
common to all tissue cells, wherever there was life and activity.

Liebig maintained that fats and carbohydrates were respir-
atory foods, that they were destroyed or burned by oxygen;
protein, on the other hand, he believed to be a plastic food, and
that its metabolism was regulated solely by the amount of
muscular work performed. This statement, however, has been
disproved by the work of many investigators, who agree in
finding that muscle work does not materially increase protein
metabolism, as measured by the output of nitrogen, at least
not under conditions where there is available fat and carbo-
hydrate to draw upon. In some conditions of the tissue cells,
as during starvation or on an exclusively protein diet, protein
alone may undergo metabolism, and the requirement of energy
for muscular work and the production of heat may both come
from the breaking down of protein. On the other hand, with
available fat and carbohydrate within reach, protein may be
metabolized in relatively small amount, while the non-nitrog-
enous material is oxidized in large measure. It is well under-
stood to-day, as pointed out by Voit, that there are many
influences acting upon the cells of the body that may serve to
modify qualitatively and quantitatively cell metabolism.

It is a testimonial to the power and influence of Liebig that
views advanced by him, though long disproved, still come for-
ward from time to time, and influence in no slight degree the
thoughts and habits of many people. There is, I think, an
underlying current of belief quite prevalent that a high protein

NUTRITION OF MAN 227

food, such as meat, is essential for full muscular vigor; that
animal food in general is, for some unknown reason, endowed
with semi-miraculous power, which renders it peculiarly fitted
to meet the needs of the body where much muscle work is to
be done. Physiologists, however, have for a long time been
occupied with a study of the many intricacies of human nutri-
tion and have acquired a fund of information as to what
substances are metabolized under different conditions of work
and rest, under varying conditions of temperature, under dif-
ferent conditions of diet, and to what extent the different
foodstuffs must be taken into the body in order to maintain
body-weight, nitrogen equilibrium, and a full measure of
physical and mental vigor. In the light of facts so obtained,
old-time views, theories founded upon false assumptions or
inaccurate data, must eventually give place to views more
closely in harmony with modern data. Facts must in time
outweigh opinions.

To-day, we recognize certain close resemblances between the
human body and machines of artificial construction; a view
which merely serves to emphasize the importance of the
physico-chemical laws which govern both, without compelling
belief in a mechanistic conception of the animal body. We
may qualify the above statement by adding that the human
machine is characterized by great complexity of function and
that some of these functions cannot, at present at least, be ex-
plained by any known methods of analysis. Consequently, we
must admit at once that the human body is something more than
a mere machine. But so far ag the general processes of nutri-
tion are concerned, there is help in the thought that the human
body, like the machines constructed by the hand of man, is
able to generate and expend energy, and that the law of the
conservation of energy is just as applicable to the human
machine as to those of simpler construction of iron and steel.
In other words, the human body is a mechanical structure,
governed, in a measure at least, by the same laws that control
unorganized matter and endowed with the power of trans-
forming energy, as from motion into heat or from heat into

228 HARVEY SOCIETY

motion, though lacking the power to create new energy. To
be more specific, the human body in the process of nutrition
transforms the potential energy of the proteins, fats and carbo-
hydrates, which constitute the food of man, into the two forms
of energy, heat and motion, in a manner analogous to that by
which the engine utilizes the energy coming from the combus-
tion of the gas, coal, or wood which serves as its fuel.

While these statements testify to a close relationship
between the animal body and a machine, so far as the trans-
formation of energy is concerned, there are several fundamental
differences in structure and function that demand attention.
The human machine has the power of growth, the power of
adding on to itself new material from the food supplied, by
which its framework or structure is made larger. Along with
this, and retained long after, is the power of repair. As growth,
under proper nutritive conditions, follows a certain general
law, it is obvious that there must be some kind of regulating
mechanism which influences and controls this peculiar process.
Whether this peculiarity of growth is dependent upon the char-
acter of the fuel or food fed, or upon some other factor, we need
not now stop to consider. The fact, however, deserves emphasis
at this point. Again, the chemical structure of the human
machine, or the make-up of its component parts, is worthy of
special attention. The living protoplasm of the individual
cells of the various tissues and organs of the body represents
a peculiar organic complex, which is subject to wear and tear
during life, and which on this account introduces an important
feature into our conception of human nutrition. The major
part of this tissue protoplasm is composed of proteins of var-
ious kinds; all nitrogenous bodies more or less closely related in
composition, but possessed of a certain degree of individuality,
dependent upon their inner or chemical structure. This brings
us to a third point of difference between the human body and
an ordinary machine, viz., that the structural material, the cell
protoplasm, of the tissues of the body is constantly changing
by processes of upbuilding and breaking down, which are
ordinarily referred to collectively as processes of metabolism.

NUTRITION OF MAN 229

It is thus apparent that in the human body we have to
deal with a machine which not merely transforms the potential
energy of the food or fuel into heat and work, but the structural
framework of the machine is constantly in a state of flux, a
state of metabolic activity, in which there is a building up
of some substances and a breaking down of others. Synthesis
and destruction are taking place constantly side by side. In
the adult, in good health, the two processes practically balance
each other, thus maintaining a certain degree of equilibrium.
In old age, all the metabolic processes are less intense, while
early in life the constructive processes are more active, thus
leading to growth. The point to be emphasized, however, is
that in the animal body the transformation of the potential
energy of the foodstuffs takes place in a machine of peculiar
complexity, the substance of which, unlike that of an artificial
machine, is itself constantly undergoing change, and the char-
acter and extent of its metabolism influences and modifies the
metabolism of the body as a whole. Here, then, the analogy
with a machine ceases, for it is quite apparent that the integrity
of the human body is of paramount importance; the needs of
its structural framework are to be considered constantly; fuel
or food is to be supplied not merely to meet the necessities for
transformation of energy, for heat and work, but to maintain
the machine in good working order, without which normal
metabolism is impossible.

From these statements, it is plain that the fuel for the human
machine, the food needed by the animal body, must not only
meet the requirements for energy, but it must also satisfy the
specific demands of the tissues and organs, in order that the
' various parts of the machine may be maintained in a high
degree of efficiency. In fact, it is easy to see that the phe-
nomena of nutrition are attributable to the activities of the
living cells of the body. As Voit has expressed it: ‘‘The un-
known causes of metabolism are found in the cells of the
organism. The mass of these cells and their power to decom-
pose materials determine the metabolism.’’ How necessary,
therefore, that these cells be kept in good nutritive condition.

230 HARVEY SOCIETY

It is the purpose of the daily food to maintain that even
balance of income and output necessary for the welfare of the
tissue cells, as well as to supply fuel for the needed energy.
This twofold function of the food must be kept clearly in
mind, for upon this depends the character and amount of the
daily food required for meeting the needs of the body.

In a general way, observation and experiment have taught
us that a mixture of the different foodstuffs, animal and veg-
etable proteins, fats and carbohydrates, together with mineral
salts and water, is the most economical physiologically and the
best adapted for supplying the needs of the organism. We
are prone to emphasize the energy needs of the body in terms
of heat units or calories, and the protein needs in terms of
nitrogen, without perhaps recognizing sufficiently the import-
ance of various unknown substances in our daily dietary,
which may play a very significant part in the maintenance of a
proper state of nutrition. It is quite conceivable that a mix-
ture of foodstuffs derived from various sources is safer, be-
cause under such condition there is less danger of the organism
being deprived of some of these unknown components, at
present of an undefinable nature, which we have reason to think
are essential for the body’s welfare.

Since carbohydrates and proteins have essentially the same
fuel value, it might be assumed that in meeting the wants of
the body for energy either one of these foodstuffs might be
used, in harmony with the taste, or faney, of the individual.
This, however, is not the case owing to the complexities of the
human machine. The body cannot long survive on a diet of
carbohydrate alone, neither on a diet of carbohydrate and fat,
because of the ever-present need for a certain amount of
protein food to make good the loss of protein, incidental to
the life of the protoplasmic tissues of the body. Physiologists
may not agree as to the exact amount of protein food required
daily, but there is no disagreement as to the necessity of sup-
plying some protein, in order to prevent protein or nitrogen
starvation. Otherwise, death soon follows.

Again, bearing in mind the far greater fuel value of fats

NUTRITION OF MAN 231

as compared with carbohydrates, it might be assumed that the
bulk of the daily food could be greatly reduced by. substituting
fats for starches and sugar. Here, again, we meet with an
obstacle in the difficult utilization of fats. Under ordinary
conditions of life, there is a limit to the amount of fat the
average individual can digest and absorb. Any attempt to
go beyond this limit is attended with serious disturbance.
Consequently, the fat of the daily diet is, more or less uncon-
sciously perhaps, restricted to a level far below that of the
carbohydrates. The customs and habits of mankind, as a rule,
all agree in giving first place, as regards quantity, to the carbo-
hydrate foods. This is in harmony with physiological teach-
ing. Carbohydrates, as a class, are relatively easy of digestion,
they are quickly available, they are completely oxidized, they
are highly palatable, and, lastly, they are generally economical
and easily obtainable foods. Voit, who has defined a food
as “‘a well-tasting mixture of foodstuffs in proper quantity
and in such proportion as will least burden the organism,”’
gave the daily diet of a laboring man as 118 grams of protein,
56 grams of fat and 500 grams of carbohydrate, with a total
fuel value of 3055 calories. This has been for many years the
generally accepted standard of the daily food requirement for
a man doing a moderate amount of work. The figures are
given here, however, as showing the usual proportion of fats,
carbohydrates, and protein entering into the daily diet of most
eivilized peoples. Naturally, individual likes and dislikes cause
fluctuations in the proportion of fat and carbohydrate, but
rarely does the daily intake of fat exceed 150 grams, carbo-
hydrate almost invariably being largely in excess. Water
is of course likewise essential, and also a certain amount of
inorganic salts, many of which are furnished admixed with the
various foodstuffs. Mineral matter is obviously not a source
of energy, but its value in the nutritive processes of the body
is not to be belittled on that account. Hardly yet have we
arrived at a full appreciation of the real significance of these
inorganic salts in controlling and modifying many of the
processes of the organism. Their absence, or a disturbance of

232 HARVEY SOCIETY

their proper proportion, may be quite sufficient to induce an
abnormality of function fatal to the life of the tissue cells.
As to the amount of the various foodstuffs required to meet
the physiological needs of the body, we find a great divergence
of opinion. There is, however, practical agreement among
physiologists that the ideal diet is one that furnishes protein
and energy sufficient to insure a condition of physiological and
nitrogenous equilibrium, with maintenance of health, strength,
and vigor, combined with ordinary resistance to disease. Any-
thing beyond such an amount is not only an unnecessary excess,
but may prove an evil of varying magnitude. Yet hereditary
customs, acquired habits, the insistent demands of capricious
appetites, have all combined to create more or less artificial
standards, for which physiological justification is frequently
sought. From the stand-point of energy requirements, it is
not difficult to see that there must be a definite relationship
between the amount of fuel needed and the amount of physical
work to be performed. The same rule holds here as in any
energy-yielding machine. The man who spends his day in
exercise on a golf course plainly requires more food, especially
carbohydrate and fat, than he who sits quietly at his desk.
The fuel value of the daily food must, on an average, be pro-
portional to the physical work performed. On this question
there is no difference of opinion. This, however, does not hold
200d in regard to the amount of protein food. Physiologists
have gradually come to see that Liebig’s dictum as to the im-
portance of protein food for muscle work is incorrect. The
energy of muscle work, of muscular contraction, does not come
from the breaking down of protein material. As already
stated, Lavoisier discovered that mechanical exercise increased
the absorption of oxygen, thus indicating that work is asso-
ciated with accelerated oxidation, or as we should say to-day
with increased metabolism. Since then, many experimenters
have demonstrated that the increased metabolism which
attends muscular work is accompanied by an increased output
of carbon dioxide and water, and not by any material increase
in the output of nitrogen. In other words, the power to do

NUTRITION OF MAN 233

muscular work is not, ordinarily at least, derived from the
breaking down of protein material, but comes from the com-
bustion or oxidation of carbohydrate and fat. Protein food,
therefore, does not need to be increased in proportion to in-
crease of muscular work. Further, the results of experiments
in my own laboratory have shown quite conclusively, I think,
that large amounts of protein food are not needed for the
maintenance of full physical vigor.

What is it then that determines the amount of protein food
required? In attempting to answer this question we are con-
fronted with several physiological peculiarities of protein which
demand our attention. When taken alone by a normal adult,
protein food undergoes oxidation with great ease, and prac-
tically none of it is retained within the body to form new
tissue; its nitrogen appears in the urine very speedily. If,
as was shown years ago, a fasting dog is fed a large amount
of protein in the form of meat, the greater part, if not all, of
the ingested nitrogen appears shortly in the urine of the
animal, 7.e., in spite of the under-nourished condition of the
dog’s tissues, little or none of the protein fed is retained.
Again, as Bischoff and Voit first pointed out, a dog of 35
kilograms, for example, fed say five pounds of lean meat, will
excrete in the following 24 hours fifteen times as much urea
as would be excreted without the heavy protein diet. In other
words, the results of these simple experiments testify to the
general truth of the statement that the extent of protein metab-
olism in the animal body is in large measure proportional
to the amount of protein food ingested. The tissues of the
adult have little or no power to hold on to protein; it cannot be
stored up as can fat and carbohydrate for future use; it is not
possible to create a large surplus for emergencies. Such being
the case, there is obviously no ground for the belief that a
surplus of protein food constitutes one of the so-called ‘‘ factors
of safety.’’ Decomposed in the body, its energy is available
in the same manner as the energy of fat and carbohydrate,
although it is not burned completely to gaseous products. The
nitrogenous part of the molecule is excreted through the kid-

234 HARVEY SOCIETY

neys, leaving a non-nitrogenous portion which behaves in the
body much as the ordinary non-nitrogenous foods. The avail-
able fuel value of protein, however, is the same as that of
carbohydrate, hence so far as the energy requirement of the
body is concerned protein has no advantage over starch and
sugar. But there are certain limitations attending the use of
protein that must not be overlooked. The large amount of
nitrogenous waste formed in the metabolism of protein entails
some strain on the excretory organs that cannot be ignored,
to say nothing of the physiological action of the nitrogenous
eatabolites, that must float about in the circulation prior to
their excretion. Certainly, protein alone is not physiologically
economical as a food. As Rubner has said, ‘‘Man cannot live
on meat alone, not because the intestinal tract cannot digest it,
but because of the physical limitations of the apparatus of
mastication.’’ However true this may be, it is quite clear that,
on the surface at least, there appears no good reason for be-
heving that a large proportion of man’s food should be made
up of protein.

Another peculiarity of protein that must be considered is
its influence on the metabolism of carbohydrate and fat. As
has already been suggested, protein food has a marked stimu-
lating effect on the metabolism of protein matter. Thus, if a
man in nitrogen equilibrium—nitrogen intake and nitrogen out-
put just balancing—is fed a larger amount of protein food,
protein metabolism is at once increased and eventually nitrogen
equilibrium is re-established, but at a higher level. Similarly,
increase in the amount of protein food augments the intensity
of the metabolism of both fat and carbohydrate. Meat, for
example, stimulates the oxidation of the non-nitrogenous
materials of the body. Thus, as has long been known, excessive
eating of protein foods tends to reduce obesity, through stim-
ulation of the metabolism of the body fat. Hence, we see that
protein is endowed with a general power of stimulating or ex-
citing the processes of metabolism, so that the combustion or
oxidation of all three classes of foodstuffs is greatly augmented
as the intake of protein is increased. How far this is a desir-

NUTRITION OF MAN 235

able attribute we shall consider later. Conversely, fats and
carbohydrates incline to inhibit the metabolism of protein mat-
ter. Thus, if nitrogen equilibrium is established at a certain
level of protein intake, increase in the amount of carbohydrate
or fat fed will at once check very decidedly the rate of protein
metabolism. Hence, while protein food increases the rate of
protein metabolism, carbohydrates and fats produce the opposite
effect. It is for this reason that in typhoid fever, for example,
there is physiological justification for relatively high carbo-
hydrate feeding, coupled with a relatively low protein intake,
as a means of preventing undue tissue waste, thereby conserv-
ing the vitality of the body and leading to a speedier
convalescence.

Again, if we adopt Rubner’s views regarding the specific
dynamic action of the foodstuffs, we may emphasize still
another peculiarity of protein. Attention has already been
called to the fact that in the utilization of protein by the body,
this form of matter must undergo a preliminary cleavage into
a nitrogen-containing residue, which is at once eliminated as
urea, and a carbonaceous residue capable of furnishing energy
for the body. According to Lusk, meat protein yields 58 per
cent. of dextrose in metabolism, It is generally understood
that the early stages in the metabolism of protein, by which
the above cleavage results and sugar is formed, give rise to
heat, but this heat is dissipated and cannot be used for the life
processes of the cells; the energy is not available for the cell
protoplasm. In other words, when protein is metabolized, about
28 per cent. of its energy content is liberated as free heat,
and cannot be used for the benefit of the body, except to give
warmth. Only 71 per cent. of the energy of the protein food
can be utilized for the benefit of cell life. When sugar, such as
saccharose, on the other hand, is taken into the body, only about
3 per cent. of its contained energy is lost as heat, in the stages
incidental to its digestion and preliminary cleavage. This
marked difference in the so-called specific dynamic action of
protein and carbohydrate in metabolism is worthy of careful
attention, as indicating a radical dissimilarity in the economic
utilization of the two classes of foodstuffs.

236 HARVEY SOCIETY

Recurring now to the amount of protein food that is needed
to supply the wants of the body, it would seem from what has
been stated that the indications physiologically are all opposed
to the free use of this foodstuff for meeting the energy require-
ments of the organism. These are supplied far more advan-
tageously and economically by the non-nitrogenous foods.
Further, with the normal adult, excessive intake of protein
does not materially increase the store of tissue protein; it is
speedily burned up and its nitrogenous portion is quickly
eliminated, while at the same time the fats and carbohydrates
of the body are burned more freely. Evidently, the true func-
tion of protein food, in the adult, is primarily to maintain the
integrity of the protoplasmic cells of the body. These cells
are composed largely of protein material, which undergoes
a more or less steady rate of metabolism during life. In these
cells are evolved all those metabolic and other processes upon
which the life of the organism as a whole depends. On these
cells rests the full responsibility for the maintenance of the
normal physiological rhythm. Without protein in some form
to rehabilitate the cells of the body, life is impossible, but the
amount needed is simply what will suffice to maintain equilib-
rium, to make good the daily loss of tissue protein. Anything
beyond this amount, seemingly, has no physiological justifica-
tion; the body has at command no facilities for making special
use of it; it is burned up as quickly as possible and so gotten
rid of. At least, such a view seems in harmony with the facts
which have been presented. These statements, however, apply
to the normal adult. With the growing child, the conditions
are plainly different. Here, there is a specifie need for protein
to supply new material for the developing and growing tissues,
and in accord with this need there is a retention of protein
such as is not seen in the adult. Further, after a wasting ill-
ness, when the tissue cells have been largely depleted, recovery
is attended with a retention of portions of the protein of the
daily food, until the cells have become filled out to their former
volume. Yet in neither of these conditions is there any appar-
ent need for a large excess of protein food, since only a small
fraction of protein is stored daily.

NUTRITION OF MAN 237

It is perhaps true, as stated by Lusk, that individual food
standards ‘‘will ever be controlled by climate, the kind and
amount of mechanical effort; by appetite, purse, and dietetic
prejudice.’’ Yet, it is equally true that there should be a
definite answer to the question, What is the amount of protein
food required, or best adapted for the physiological needs of the
body? There is no argument as to the importance of the
problem, from either a physiological, economical, or sociological
stand-point. Every civilized country has considered the ques-
tion, and physiologists from every nation have contributed
towards its solution. It is somewhat strange, however, that the
main work done has been in the direction of statistical inquiry.
The dietetic habits of mankind have been studied, and great
masses of data have been brought together, showing what the
average man of different countries is in the habit of eating.
While all this is very illuminating and interesting, it does not
promise much help in determining what amounts of food are
required to meet the real needs of the body, and to serve most
economically and healthfully the best interests of the organism.
Public opinion and even scientific opinion have, however,
shaped themselves largely on the results of these statistical
inquiries. Opinion even sanctions, in the words of Sir James
Crichton-Browne, basing the science of dietetics on common
observations, and on the hereditary customs and habits of man-
kind. There is a tendency to magnify natural instinct and
primitive experience, as guides in the choice and construction
of the daily dietary, esteeming them of greater value than any
help chemical or physiological science can offer. In harmony
with this tendency, statistical data have been much in evidence,
for many years, as representing the food requirements of man.
Why this should be is somewhat difficult to understand, sinee
man is a creature of habits and might quite naturally have
acquired some customs the reverse of physiological. However
this may be, Rubner in Germany, Atwater in America, Lichten-
felt in Italy, and others have advocated 125 grams of protein
food daily for the laboring man, because the laboring man of
these countries consumes on an average this amount of protein.

238 HARVEY SOCIETY

This conclusion does not seem very scientific, nor very con-
vincing, but all the same it finds wide acceptance. Further,
for men at hard labor still higher quantities of protein are
recommended by Voit, Rubner, and Atwater, up to 165 grams
of protein per day. Rubner, indeed, has stated ‘‘that a large
protein allowance is the right of civilized man,’’ and the general
idea of a ‘‘luxus consumption’’ as applied to protein food
finds no lack of supporters. Opinions seemingly outweigh facts,
while reasoning along physiological lines fails to prove con-
vineing to those who bow to the testimony of hereditary cus-
tom and acquired habit. Civilized man may have assumed the
right to a large allowance of protein, as he has assumed the
right to alcohol, tobacco, and other questionable practices, but
this is not evidence of physiological value.

What, for example, is the significance of the chain of events
which follow the ingestion of protein food? Its prompt cleav-
age in the alimentary tract, the denitrogenation of the cleavage
products in the intestine and liver, and the prompt conversion
of the nitrogenous fragments into urea, all bespeak a quick
and ready. method of ridding the system of the greater part of
this nitrogen, for which it apparently has no need. Further,
as has been indicated previously, the facts regarding nitrogen
equilibrium can be interpreted only as showing that excess
of nitrogen is not stored in the body. Of what use then is a
large allowance of protein or nitrogen? In the words of Folin,
‘“The ordinary food of the average man contains more nitrogen
than the organism can use, and increasing the nitrogen still
further will therefore, necessarily, only lead to an immediate
increase in the elimination of urea, and does not increase the
protein catabolism involved in the creatinin formation, any more
than does an increased supply of fats and carbohydrates. The
normal human organism can be made at almost any time to
store up fats and carbohydrates. The catabolism of these
products consists chiefly of oxidation, a decomposition which
sets free large quantities of heat, which can be converted into
mechanical energy useful to the organism. The hydrolytic
removal of nitrogen from the protein involves by comparison a

NUTRITION OF MAN 239

very small transformation of energy, and yields a non-nitrogen-
ous rest of great fuel value. This non-nitrogenous rest derived
from protein may partly be directly transported to the different
tissues and thus at once supply oxidative material where needed,
but in all probability is partly converted into fats, or at least
into carbohydrates, and then becomes subject to the laws gov-
erning the catabolism of these two groups of food products.”’
The value attaching to the major part of the protein is, there-
fore, that of the non-nitrogenous portion which comes from the
denitrogenation of the cleavage products.

Is it possible that this denitrogenized residue of the protein
molecule plays some part in the organism which fats and carbo-
hydrates cannot fill, and that on this account there exists a real
demand for a large allowance of protein? Some years ago, I
ventured the opinion that there are only two possible reasons
for assuming a need for the high exogenous catabolism of
protein so commonly observed. The one is that the carbona-
ceous residue, left after the cleavage of nitrogen from the pro-
tein, is possessed of some quality which renders it better adapted
for meeting the needs of the body than either fat or carbo-
hydrate. But experiment has furnished no evidence to war-
rant such an assumption. The other possibility is that the body
may derive some advantage from the presence in the tissues
and fluids of the nitrogenous cleavage products of the protein.
It is equally plausible, however, that the many nitrogenous
fragments, formed in the efforts of the organism to prevent
undue accumulation of reserve protein, may in the long run do
as much harm as good. A high exogenous metabolism thus
becomes subject to the suspicion that, at the level ordinarily
maintained, it constitutes a menace to the preservation of that
high degree of efficiency which is the attribute of good health.
Again, it is well to remember that while, normally, excess of
nitrogen in the food is quickly converted into urea and thus
eliminated, the continuous excessive use of protein may lead,
as Folin has suggested, to an accumulation of a larger amount
of floating protein than the organism can with advantage retain
in its fluid media. This being so, it is quite possible that the

240 HARVEY; SOCIETY

continuous maintenance of such an unnecessarily large supply
of unorganized protein material may sooner or later weaken one
or more of the living tissues of the body.

Experiments to determine the physiological needs of the
human body for protein have been attempted at various times,
but mostly in a semi-apologetic fashion, and under the domi-
nance of a faith in the virtue of high protein that has obseured
the vision and weakened the force of the conclusions. Grad-
ually, however, data from many sources, more or less in agree-
ment, have combined to emphasize the fact that in man nitrog-
enous equilibrium can be maintained, for short periods of
time at least, on amounts of protein food far below the accepted
standards. Such a conclusion, while by no means proving
that the smaller amount of protein is adequate for meeting
all of the needs of the body, or maintaining the highest degree of
efficiency, is obviously very significant. If the taking of a
relatively small amount of protein day by day is followed by
a minus nitrogen balance, it would be evidence most convine-
ing that the amount of protein in question was not adequate,
that the body was compelled to draw upon its store of protein
to make good the deficiency. Plainly, such a procedure long
continued would bankrupt the organism. On the other hand,
we should be equally ready to admit that a daily plus nitrogen
balance, obtained with small amounts of protein, is to be given
equal weight, as at least indicating the probability or possibility
that the protein fed was adequate for the body’s needs. It
might be argued that the simplest way to determine the mini-
mum amount of nitrogen, or protein, needed daily by man
would be to ascertain the output of nitrogen during fasting.
Such data, however, have little value in this connection, since in
long fasting, where no non-nitrogenous food is being consumed
and the store of tissue fat and carbohydrate is exhausted, the
body must of necessity live solely at the expense of the tissue
proteins. Still, in Sueci’s case, with a body-weight of 63
kilograms, the nitrogen eliminated on the tenth day of fasting
was in one experiment 7.4 grams, in a second experiment 5.4
grams, and in a third 7.1 grams; amounts equal approximately

NUTRITION OF MAN 241

to the metabolism of 46 grams and 34 grams of protein per
day respectively.

The taking of non-nitrogenous food naturally diminishes
the dynamogenic utilization of the tissue protein, and the
proper method to be employed in arriving at a clearer con-
ception of the physiological requirement for protein is to study
the effect of a lowered intake of protein, when admixed with
suitable quantities of non-nitrogenous foods. By such a method
Siven, with a body-weight of 60 kilograms, found it possible to
establish nitrogen equilibrium on 6.2 grams of nitrogen daily,
for a short period of time, without taking any undue excess of
either fat or carbohydrate. This amount of nitrogen corresponds
to 38.75 grams of protem. Siven’s experiments, made in 1900,
attracted considerable attention, but they availed little in in-
fluencing opinion, which was as strongly as ever opposed to
the idea that continued health, strength, and general efficiency
can be maintained on a low protein intake. Siven’s results,
however, are in general harmony with a large number of
experiments by various observers, some of earlier date and some
later, all duly recorded in the literature, and all testifying to
the possibility of maintaining the body in nitrogen equilibrium
on amounts of protein far below the accepted standard.

Probably, the strongest argument against the safety of a
continued low intake of protein was that based on the experi-
mental work of Munk, Rosenheim, and of Jigerroos with dogs,
all of whom found that with these carnivorous, high-protein
feeders the giving of protein just sufficient to maintain nitrogen
equilibrium was attended by a gradual loss of strength and ser-
ious digestive disturbances. During the past eight years, these
results have been widely quoted as confirming the view that
more protein is needed than suffices to maintain nitrogenous
equilibrium; that a daily surplus is called for, if health and
strength are to be secured. My own later experiments, how-
ever, have, I think, clearly shown that the unfortunate results
reported by the above observers were due entirely to other
causes than the diet. Kept under suitable hygienic conditions,
it is quite possible to maintain dogs—in my own experiments

242 HARVEY SOCIETY

for a year—not only in nitrogen equilibrium on amounts of
protein and non-nitrogenous food, per kilogram, far below the
quantities employed by Munk and Rosenheim, but on this
relatively low protein diet they may gain in body-weight and
lay by some nitrogen. Further, there was no loss in the power
of digestion, no falling off in the utilization of either fat or
protein. In other words, there was no evidence of diminished
power of absorption from the intestinal tract, no evidence of
lowered utilization of the ingested food. The more or less
broad deductions inimical to low protein, so widely drawn from
the experiments of Munk and Rosenheim on dogs, and applied
freely to mankind are entirely unwarranted and without foun-
dation in fact. It is, however, interesting to note the failure
of the dogs—in our experiments—to thrive on the purely
vegetable dietary made use of, viz., peas, beans, and wheat;
there seemed to be a necessity for some little admixture of
animal food, such as meat or milk. Whether this means a
difference in the physiological behavior of the vegetable protein,
or whether the animal food contained something essential,
which was lacking in the vegetable products, we need not stop
to consider.

It is now, I think, perfectly well established that man can
maintain, for a time at least, a condition of nitrogen equilib-
rium on a relatively small amount of protein food, provided
carbohydrates and fats are eaten in such amounts as will
supply the energy requirements of the body. Less clear, in the
minds of many, is the effect on health and efficiency of a low
protein diet, when continued for long periods of time. In other
words, would not the effect on the race eventually prove dis-
astrous, if a daily dietary was adopted which contained say
only 50 to 60 per cent. of the protein called for by the Voit
standard? This question I have attempted to answer, so far
as a scientific experiment can afford an answer, by a long-
continued investigation on a large body of men of different
types, different nationalities, and different occupations. The
results are all on record, and I may merely summarize by stat-
ing that daily analyses of income and output for twenty

NUTRITION OF MAN 243

individuals during a period of nine months, with careful
observations on the health, strength, and endurance, etc., of
the subjects, have furnished a fund of information from which
definite conclusions seem justified. Further, with several
individuals, notably with one, the experiment has continued
with some limitations for seven years. I am inclined to be-
lieve, on the basis of the results obtained, that the average
need for protein food by adults may be fully met by a daily
metabolism equal to an exchange of 0.10-0.12 gram of nitro-
gen per kilogram of body-weight. This means a breaking down
of three fourths of a gram of protein daily, per kilogram. Ex-
pressing it somewhat differently, the required intake of protein
food amounts to say 0.85 gram per kilogram of body-weight.
Hence, a man weighing 70 kilograms, or 154 pounds, would re-
quire daily 60 grams of protein food; i.e., just one-half the
amount called for by the Voit standard, and still further below
the quantities implied as essential by the every-day practices of
a large proportion of mankind. The facts brought out by this
investigation testify to the possibility of maintaining nitrogen
equilibrium in man over long periods of time on a daily
metabolism of 0.1 to 0.12 gram of nitrogen per kilogram of
body-weight, provided sufficient non-nitrogenous foods are eaten
to supply the energy needed by the body. <As I have said else-
where, the facts obtained ‘‘are seemingly harmonious in indicat-
ing that the physiological necessities of the body are fully met
by much more temperate use of food than is commonly prac-
tised. Dietary standards based on the habits and usages of
prosperous communities are not in accord with the data fur-
nished by exact physiological experimentation. Nitrogen
equilibrium can be maintained on quantities of protein food
fully 50 per cent. less than the every-day habits of mankind
imply to be necessary, and this without increasing unduly the
consumption of non-nitrogenous food. The long-continued
experiments on many individuals, representing different types
and degrees of activity, all agree in indicating that equilibrium
can be maintained indefinitely on these smaller quantities of
food, and that health and strength can be equally well pre-

244 HARVEY SOCIETY

served, to say nothing of possible improvement. The lifelong
experience of individuals and of communities affords sufficient
corroborative evidence that there is perfect safety in a closer
adherence to physiological needs in the nutrition of the body,
and that these needs, so far as protein food is concerned, are
in harmony with an endogenous metabolism, or true tissue me-
tabolism, in which the necessary protein exchange is exceedingly
limited in quantity. There are many suggestions of improve-
ment in bodily health, of greater efficiency in working power,
and of greater freedom from disease, in a system of dietetics
which aims to meet the physiological needs of the body with-
out undue waste of energy and unnecessary drain upon the
functions of digestion, absorption, excretion, and metabolism
in general; a system which recognizes that the smooth running
of man’s bodily machinery calls for the exercise of reason and
intelligence, and is not to be intrusted solely to the dictates of
blind instinct, or to the leadings of a capricious appetite.
Recurring once more to some of the objections raised against
a daily consumption of smaller amounts of protein food by the
human race, it is said that a considerable excess of this type
of food is essential, in order to supply a proper variety of the
special amino-acids required for the construction of the char-
acteristic proteins of the blood, and of the different organs and
tissues of the body. This is an objection that carries some
weight and should be given due heed. To be sure, it might be
said that since individuals have lived and thrived for long
periods of time on small amounts of protein, there cannot be
any serious danger, still the objection raised has a good physio-
logical basis. The work of Fischer, Abderhalden, Osborne,
Levine, and others, has taught us that the individual proteins,
of animal and vegetable origin, differ widely in the character
and quantity of the amino-acids of which they are composed.
Hence, there is reason in the statement that the body must be
supplied with such a variety of amino-acids as will enable the
different tissues and organs to construct the specific proteins
they require. If the building stones needed are not supplied
by the food, how can the body maintain its structure? We are

NUTRITION OF MAN 245

somewhat in the dark as to the methods by which tissue pro-
teins are repaired. The old-time view that the proteins of the
food were simply transformed into the proteins of the blood,
and these in turn converted into the proteins of the tissues, has
been supplanted by a new conception, viz., synthesis. Note the
radical difference in the structure of the individual proteins:
Zein of corn meal, for example, contains in its molecule 19.5
per cent. of leucine, 26 per cent. of glutaminie acid, 9.8 per
cent. of alanine, no glycocoll, no lysine, and no tryptophane.
It is what is known as an incomplete protein. Casein of milk,
on the other hand, though lacking glycocoll, contains within its
molecule both lysine and tryptophane; 6 per cent. of the former
and 1.5 per cent. of the latter. Further, instead of the 26 per
cent. of glutaminic acid present in zein, casein contains only
15.5 per cent., and of leucine only 9.3 per cent. These are
merely suggestions of the differences which exist in the chemical
structure of the individual proteins; differences which imply
unlike physiological behavior and raise the question of com-
parative nutritive values. With such marked variations in
composition, especially the complete absence of certain amino-
acids from some proteins, there is ground for the assumption
that a daily dietary containing only a small amount of protein,
and the latter perhaps limited in quality, might prove hazard-
ous. To be sure, even a narrow dietary is pretty liable to con-
tain several varieties of protein, but we may waive this and
consider the validity of the suggested danger. It would seem
that here is one of the many questions which might be answered
by direct experiment, thus allowing facts to supplant opinions.
Thanks to the recent work of Osborne and Mendel at New
Haven, and of McCollum at Wisconsin, we have some very
interesting facts that supply a definite answer to these questions.

Feeding experiments carried out by Osborne and Mendel
on white rats, for long periods of time, have shown that a single
protein, reinforced by protein-free milk to provide the acces-
sory portions of the diet, is quite sufficient to maintain adequate
growth. This was found to be true of the casein of milk,
lactalbumin, crystallized egg albumin, crystallized edestin from

246 HARVEY SOCIETY

hempseed, the glutenin of wheat, and glycinin from the soy.
bean. McCollum, feeding casein as the sole protein to pigs,
found increases of the body protein of 20 to 25 per cent.
Further, in the summary of his conclusions, this investigator
states, “‘that the results of experiments in feeding the mixture
of proteins occurring in individual grains, in quantity equiv-
alent to the lowest possible level of protein metabolism of which
the animal is capable, do not indicate as wide differences in the
nutritive values of the protein of the wheat, oat, and corn ©
kernels as would be expected from the known chemical differ-
ences in these proteins.’? But not all proteins are able to
promote growth. Thus, as Osborne and Mendel have found, the
gliadin of wheat which is notably lacking in the two amino-
acids glycocoll and lysine, and the hordein of barley, which
closely resembles gliadin, will suffice to maintain an animal, but
cannot supply that which is essential for growth. Zein, of
maize, which lacks three important amino-acid complexes, viz.,
glycocoll, lysine, and tryptophane, cannot alone cause growth,
neither will it suffice to maintain the animal. Yet, as MeCol-
lum has shown, ‘‘the animal can utilize the nitrogen*of zein
very efficiently for repair of the losses due to endogenous or
tissue metabolism,’’ the average utilization of zein nitrogen
for this purpose being about 80 per cent.

Consider for a moment what results of this character imply
regarding the power of the organism to build up from a single
dietary protein such diverse nitrogenous tissues as enter into
the structure of every animal organism. In the words of
Osborne and Mendel, ‘‘ We have seen rats grow for months with
easein—thoroughly purified and glycocoll-free—as the sole
source of these amino-acids. During this time, one animal even
brought forth two broods of young and secreted milk in suffi-
cient quantity to bring her young to the age when they were
able to care for themselves. Another pair of rats maintained 178
days (one-sixth of the average life of an albino rat) on gliadin
as the sole protein of the diet produced healthy young and
successfully reared them.’’ These facts are strongly suggestive
of a power of synthesis possessed by the cells of the organism

NUTRITION OF MAN Q47

far beyond any previous conception. Think what it means for
an animal to grow from small size to the adult form, quadrup-
ling its weight, on a diet in which the nitrogen is supphed
solely by a simple protein like edestin! What is the character
of the process, or processes, by which the tissue cells ‘‘ perfect
the synthesis of purines and nucleoproteins, perchance of
phosphoproteins and nitrogenous phosphatides, and of ferru-
ginous proteins (like hemoglobin) from iron-free protein pre-
cursors and inorganic iron’’? (Osborne and Mendel.)

Equally suggestive are the results obtained with a so-called
incomplete protein, such as gliadin, where health and equilib-
rium are maintained, with the capacity to produce and rear
young, but without the power of growth. As stated by Mc-
Collum, ‘‘The fact that certain proteins, lacking in one or more
cleavage products known to be necessary to the formation of
the proteins of the animal body, are of relatively high efficiency
in preventing loss of body nitrogen due to endogenous metab-
olism, yet are insufficient for growth, forces one to the con-
clusion that the processes of replacing nitrogen degraded in
cellular metabolism are not of the same character as the proc-
esses of growth. It seems also to be a necessary conclusion
that the processes of cellular catabolism and repair do not
represent a series of chemical changes involving the destruction
and reconstruction of an entire protein molecule.’’ These cur-
rent views regarding nutrition, and the facts upon which they
are based, only serve to strengthen the position that there is no
physiological need for a surplus of protein in the daily dietary.
The power of synthesis possessed by the animal organism is
such that even with a minimal supply of protein, and that per-
haps of a character not best adapted for the needs of the body,
the tissue cells can be relied upon to make good the deficiency
by processes peculiarly their own; a type of a factor of safety
which has real physiological significance.

If the newer data, which have been rapidly accumulating,
truly represent the protein requirement of the body, would
it not be the part of wisdom gradually to adopt dietary prac-
tices more nearly in accord with the physiological findings?

248 HARVEY SOCIETY

To this, however, we hear many objections, some based upon
opinions and impressions of varying validity, some so mani-
festly biased that they carry little weight to an unprejudiced
mind, while others are predicated upon findings which are inter-
preted at least as being opposed to the conclusions I am empha-
sizing. Opinions and impressions, together with arguments
that are more or less visionary, we have not time to consider,
but there are certain statements of fact that are deserving of
more than passing notice. Take, for example, the interesting
observations of Albertoni and Rossi on the nutritive conditions
of Italian peasants, who by force of circumstances are com-
pelled to live on a very limited and simple diet, such as is
afforded by the immediate products of the land, viz., cornmeal,
green vegetables, and olive oil. The diet, which is poorly pre-
pared and unattractive, is low not only in protein, but in all
the nutrients; it is exceedingly monotonous, is never reinforced
by milk or eggs, and rarely contains any meat. The digesti-
bility of the food is low and it is plainly poorly utilized. The
statistics of food intake for thirteen persons, comprising three
families, showed an average ingestion of 73 grams of protein
per day for the men, with an average body-weight of 57 kilo-
grams, with 8 grams of nitrogen metabolized. The observers
state that the social, physiological, and psychical status of these
people is anything but satisfactory. If now, without increase
in the total calorific value of the day’s ration, 100-200 grams
of meat are substituted in the diet daily, a marked improvement
is to be observed, among other things the digestion and utiliza-
tion of all the foodstuffs being increased. Albertoni sees in
these results convincing evidence of the detrimental effects of
a low protein diet when long continued, and by inference at
least the lack of stamina and general unsatisfactory status
of these people are to be ascribed to their low nitrogen intake.
This view is in harmony with a current tendency to ascribe to
low protein the responsibility for whatever unsatisfactory
feature may show itself whenever a low nitrogen intake is one
of the attendant conditions. As a matter of fact, we are deal-
ing here with a people who are through the poverty of their

NUTRITION OF MAN 249

surroundings manifestly undernourished. They are dependent
for their subsistence upon a daily dietary which is inferior,
poorly balanced, and difficult of digestion. The fact that the
diet is low in protein is merely an incident of minor importance
and without any necessary causal relation to the effects which
apparently follow its use. What resemblance is there between
this narrow, ill-balanced, and difficultly available diet of the
Italian peasants and a daily dietary of equal nitrogen content,
but made up of a palatable variety of animal and vegetable
foods of easy digestibility and ready availability? The real
trouble with the dietary of Albertoni’s subjects is the char-
acter of the daily food and not its nitrogen content. The food
of man, whether high or low in the proportion of protein, should
be of a character readily assimilable if it is to fulfil satisfac-
torily the requirements of an ideal diet. Further, it must not
be lacking in any one essential component; a danger which is
greatly enhanced when the daily dietary is constantly limited
to a few articles of food. No race or nation can hope to attain
a high state of physical or mental development on a diet so
manifestly indigestible, so lacking in variety, and so poor in
total fuel value as that of these Italian peasants.

Much the same objection must be made to the conclusion
drawn by McCay, from the results of his interesting study of
the nutrition of the Bengali. This investigator found that the
natives of Lower Bengal living on the ordinary diet of the
province, viz., rice and a peculiar form of pulse, known as
dhall, practically exist all their lives on a metabolism of about
40 grams of protein per man daily. As McCay states, these
results confirm the view that it is quite possible for man to
subsist throughout his life on a diet containing not more than
one-third the amount of protein called for by the generally
accepted standards. But the poor physical development of the
race, the limited capacity of the individuals for manual labor,
their low resistance to disease and infection, the condition of
their blood and tissues, all testify to a degree of inferiority as
compared with European standards of health and strength
which demands explanation. McCay finds the explanation in

250 HARVEY SOCIETY

the low intake of nitrogen, in the small amount of protein in-
gested. To use his own words, ‘‘The physical development is
only such as could be expected from the miserable level of
nitrogenous interchanges to which he attains.’’ Here, again, only
in more striking fashion than is seen with the Italian peasants,
we are dealing with a race which by force of circumstances is
compelled to subsist upon a daily dietary utterly unsuited for
meeting the needs of the body. The diet is, as already stated,
composed almost entirely of rice and dhall; the latter pecu-
larly undigestible. Full 25 per cent. of the ingested nitrogen
passes through the alimentary tract unabsorbed. In the words
of McCay, the diets of the Bengali ‘‘are one and all bad in
every respect, and particularly bad in that the large waste in
the alimentary canal allows excessive micro-organismal develop-
ment and formation of toxic compounds. .... A splendid op-
portunity for the growth of micro-organisms with its attendant
intestinal putrefaction and toxemia is provided, predisposing
to numerous pathological conditions, such, for instance, as
septic ulceration of the gums, intestinal eatarrh and diarrhea,
dysentery, and anemia. These are all exceedingly common dis-
orders met with in the outpatient department of a general
hospital.’’ As I have said in another connection, ‘‘ What bear-
ing have these results, interesting and important though they
are, upon the merits of a proper low protein intake, where the
diet is well balanced and with a proper degree of digestibility
and availability? There is no difficulty, under most conditions
of life, in maintaining a relatively low nitrogen intake with an
adequate fuel value, by the use of foodstuffs that are reasonably
digestible and available, with freedom from excessive waste in
the intestine. Surely then this peculiar, irrational diet of the
Bengali, with its large proportion of rice and indigestible
dhall, cannot be considered as typifying a true low protein diet.
Rather is it an example of an unbalanced, unphysiological
ration, the ill effects of which might reasonably be expected.”’
Further, is it not quite likely that in the long-continued use of
such a narrow dietary, with its very limited variety of food-
stuffs, some one or more essential substances, upon which the

NUTRITION OFZMAN 251

very life of the organism depends, may be omitted and thereby
the health of the organism endangered? Is it not quite as
plausible to assume that the Bengali owe their poor nutritive
condition to the lack of some necessary element which their
restricted dietary fails to provide, or to supply in adequate
amount, rather than to their low nitrogen metabolism?

How often in our blind search after the truth do we err
in the conclusions we draw from the data collected, sometimes
magnifying the unimportant at the expense of what is really
vital, sometimes overlooking entirely what should attract our
attention most markedly. In the disease known as beriberi,
so common at one time in Japan, especially among the class of
people who subsisted largely upon rice, it was thought that
the low protein diet which these people were accustomed to was
responsible for the disease. When in connection with the
Russian-Japanese War the daily ration of the Japanese sailors
and soldiers, through the introduction of American beef and
other food products, was reconstructed, raising the protein-con-
tent to a level approximating that of the European nations,
beriberi began to disappear. These facts have been brought
forward repeatedly as evidence of the deleterious effect of a
low protein diet, the rice acting as a factor simply because it
was poor in protein, and hence a daily diet composed largely
of this foodstuff must necessarily be deficient in nitrogen.
Now, however, as the work of Eykman and others hag shown, it
is not rice in general that causes beriberi, but rice that has
been prepared in a certain way. It is only the polished rice,
i.e., rice that has been cleaned of its cuticle and outer layers
by a process of milling that is harmful. In the words of Aron,
‘“‘We must regard the second process of polishing and milling
as that which changes a harmless foodstuff to one harmful
under certain cirecumstances.’’

Quoting from Heiser, ‘‘The advances made during the past
year in placing the etiology of beriberi upon a scientific basis
have now proceeded sufficiently to warrant the inference that
prophylactic medicine has the knowledge at its command to
place this scourge among the preventable diseases.’’ It has

252 HARVEY SOCIETY

now been demonstrated experimentally that beriberi in man and
polyneuritis in fowls, when associated with rice as a diet, are
due to the removal of the outer portion of the grain of the
pericarp. Prior to 1910, beriberi was very common throughout
all of the public institutions of the Philippines; also among
the Philippine troops of the United States Army. Since that
date, when an executive order was issued by the Governor-
General of the Philippine Islands prohibiting the use of
polished rice in all public civil institutions, beriberi has prac-
tically disappeared. To quote again from Dr. Heiser, ‘‘In one
particular asylum, with 700 inmates, beriberi has almost con-
stantly been present during the past ten years. Since June,
1910, unpolished rice has been used, and a few weeks after its
use was begun beriberi disappeared, and since that time no
further cases have been reported.’’

The work of Chamberlain and Vedder, in the Philippines,
shows that polyneuritis gallinarum may be prevented by means
of an extract of rice polishings, containing only those sub-
stances which are soluble in cold water and cold alcohol.
Further, the neuritis-preventing substance was found to be
capable of dialysis through a parchment membrane, showing
that it must be ecrystalloidal in nature. The recent work by
Funk, just published, shows that the essential ingredient in the
rice polishings is an organic base; a substance plainly of great
physiological importance. <A daily diet in which polished rice
is the main ingredient may prove deleterious simply because it
fails to provide this important compound that resides in the
outer layers of the rice berry, or which might be supplied by
certain other foods, such a beans, meat, ete. The smaller
amount of nitrogen furnished by the rice diet is merely an
incident having no connection whatever with the cause of the
disease. As illustrating the physiological importance of little
things in diet, it is only necessary to state that the amount of
this organic, nitrogenous base in rice is probably not more than
0.1 gram per kilogram. Further, as Funk has shown, the
curative dose of the active substance is very small; a quantity
which contains only 4 milligrams of nitrogen is sufficient to

NUTRITION OF MAN 253

cure pigeons, in which polyneuritis has been induced by feeding
polished rice.

The above facts serve to illustrate and emphasize both the
importance and the obscurity of certain nutritive factors which
are as yet hardly recognized. Observations and experiment
bearing upon the nutritive value of any given foodstuff, or
upon any specific dietary, must be carefully safeguarded to
avoid possible pitfalls which may lead to error. The inorganic
salts which are so variable in character and amount in the
different animal and vegetable foods are especially liable to be
overlooked or inadequately provided for. These mineral
nutrients play a part in the organism which is hardly yet fully
recognized or appreciated. ‘‘One may, it is true, imitate the
‘ash’ of milk or blood; but the elements occur here in com-
binations quite different from those prevailing in the tissue
fiuids themselves, or in the native foods. The balance of acid
and basic groups, the changing need for individual elements
like phosphorus, calcium, chlorine, and iron, furnish a series of
complex variables which are probably as indispensable to cer-
tain aspects of nutrition as they are unappreciated. If to all
this is added the uncertain significance of the as yet largely
unidentified compounds such as cholesterol and phosphatides
which occur in all natural food mixtures, the experimental
difficulties begin to appear in their true light’’ (Osborne and
Mendel). This is well illustrated by the recent feeding experi-
ments carried on at New Haven by Osborne and Mendel, where
isolated proteins, reinforced by starch, fat, and a salt mixture,
were fed to white rats. The young animals given a single
protein could be maintained at uniform size and body-weight
for long periods of time, but they failed to grow. The natural
inference was that the single protein was inadequate, but
evidence, gradually accumulated, eventually pointed to some-
thing other than the character of the protein, fat, or carbo-
hydrate as the responsible agent. By simply feeding milk from
which all protein had been removed, thus leaving only the
inorganic salts, milk-sugar and other as yet unknown com-
ponents of the milk, the necessary accessory elements were

254 HARVEY SOCIETY

provided and growth at once became possible. In the words of
Osborne and Mendel: ‘‘Rats which have developed marked
symptoms of decline on mixtures of isolated food substances
containing a single protein have been revived in a manner
little short of marvellous by the substitution of the protein
free milk in place of part of the previous (non-protein) food.
Instances have occurred where successful realimentation has
thus followed in animals practically moribund.’’

Again, why should herbivorous animals, accustomed to a
mixed vegetable diet, show such striking differences in general
vigor, rate of growth, strength of offspring, capacity for milk
secretion, ete., when fed through a period of three to four years
on comparably balanced rations from restricted sources? One
reads with interest and surprise the striking results recently
presented by Messrs. Hart, McCollum, Steenbock, and
Humphrey obtained with young heifers, when fed on nutrients
limited to a single plant, namely, corn, wheat, and oats.
Although the nitrogen or protein content and fuel values were
essentially the same, yet it soon became perfectly evident that
the nutritive or physiological value of the different feeds was
radically unlike. Animals receiving their nutrients from the
corn plant were strong and vigorous, in splendid condition all
the time, and reproduced young of great weight and vigor.
Those receiving their nutrients from the wheat plant were
unable to perform normally and with vigor all the above
physiological processes. Animals having their nutrients from
the oat plant were able to perform all the physiological proce-
esses of growth, reproduction, and milk secretion with a cer-
tain degree of vigor, but not in the same degree as manifested
by the corn-fed animals. This was the result obtained from the
continued use of the specified rations during a period of three
years. Wheat-fed animals changed to a corn diet showed
marked improvement, both in the size of offspring and in milk
secretion. The converse was true when corn-fed animals were
transferred to a wheat ration.

How are we to explain such marked differences in the re-
sults obtained by the use of rations comparably balanced unless

NUTRITION OF MAN 255

we assume the presence of various elements, or groups of
elements, in these specific foods, ‘‘whose proper or improper
combination may make for vigor, resistance, and splendid con-
dition, or for weakness, low resistance, and poor condition in
the individual’’?

Tilustrations such as these serve the twofold purpose of
emphasizing the paucity of our knowledge regarding all of
the nutritive requirements of the body, and the necessity of
applying to the study of the problem the same careful and
scientific control that should prevail in every physiological
inquiry, lest we err in the views we adopt.

AGE, DEATH AND CONJUGATION IN THE
LIGHT OF WORK ON LOWER
ORGANISMS *

PROFESSOR H. S. JENNINGS
Johns Hopkins University

ie oes coke we are all interested in the subject

of age and death. But the interest is of the kind that
my friend Professor Lovejoy calls the interest of the repul-
sive. If we were free in the matter, we should doubtless pre-
fer neither to hear nor know anything about the subject. But
since to continue in that state of blissful ignorance and imex-
perience is impossible, we are driven to ask certain questions
on the matter. What is the reason for our weakening and
disappearing, along with all the visible living things that sur-
round us? Why might we not as well continue indefinitely
our interesting careers, instead of dropping off just as we be-
come able to do something worth while? And must it be so
inevitably? Is it grounded in the nature of life that all that
live must die?

From the ancient seekers after the fountain of youth to
the modern physiologists working toward the preservation of
life, the prolongation of its processes, and the suppression of
death, there have not lacked men who cherished the bold
thought that death may be no essential part of life, that pos-
sibly some means may be found for counteracting the process
of aging, for excluding death. And these men but express
a secret wish of all mankind.

In this condition of affairs, a field of great interest was
opened when the microscope revealed to us a world of organ-

* Delivered March 2, 1912.
256

AGE, DEATH AND CONJUGATION 257

isms which seem at first view not to get old and die. As we
follow them from generation to generation, the infusorian, the
bacterium, seems not subject to the law of mortality. These
creatures live for a time, then divide into two, and continue
to live. Death appears, as we watch them, to occupy no place
in their life history, save in consequence of accident.

This seemed to settle one of the great questions; whether
age and death are inherent in life; inseparable from it. Here
apparently was life without death; here was perpetual youth.
If this can be in the infusorian, why not in other organisms,
why not in man? Or if our thoughts be not so bold as this,
may we not by study of the infusorian at least satisfy to a
certain degree our understanding, learn perhaps something
of the origin, cause and nature of age and death, and of the
nature of that kind of life which avoids it? It is because
T have devoted some years to a study of these matters in such
creatures that I venture to speak to you on this subject.

You remember that one of the famous early essays of
Weismann was upon the question I have just raised. He
tried to show that death is not at all necessarily involved in
living; that natural death originally did not exist, and does
not exist now in these lower creatures; with theology he held
that death was acquired in the course of time, and the Satan
that ‘‘ brought death into the world and all our woe ’’ was
no other than natural selection, acting for the benefit of the
race, as distinguished from that of the individual. The body
in the course of time becomes worn, battered, crippled. It is
well to have at intervals a clearing out of this worn stock; new,
fresh bodies replace the battered ones and a race which under-
eoes regularly this renewal must prevail and perpetuate itself
in the place of those that do not; such is the conception of
Weismann. Thus, too, the sum of happiness in the world is
kept at the highest mark, since the fresh and perfect can enjoy
much more than the worn and crippled.

But according to this view, if organisms could but live in
such a way as to keep the body fresh and uninjured, there

258 HARVEY SOCIETY

would be no need for death. And the organisms which have
succeeded in doing this are the infusoria and their relatives.
These, in the famous phrase of Weismann, are ‘‘potentially
immortal.’’

But another fact in the lives of these creatures attracts
strongly the attention of the observer. These same unicellular
organisms that appear to live forever do likewise go through
the same process of sexual union that we find in higher ani-
mals. Now this sexual union has proverbially stood as the
_ token of mortality; it is the preparation for the new genera-
tion, and pretigures the disappearance of the old one. You
will recall the famous remark of Alexander the Great upon
this point.

Why then should this take place in these ever-living ecrea-
tures? The fact that it does was held by many to indicate
that to consider these creatures ever-living was a mistake; they
predicted that these animals would be found not potentially
immortal, but subject to death at the end of a certain term,
just as are higher animals. It is interesting to discover here,
as in so many other cases, that the diverse possible opinions on
the subject were formulated and maintained before investiga-
tion had obtained evidence as to the facts in the ease.

But men were not content to speculate; and Maupas in one
of the great investigations of biology (1883 to 1888) undertook
to determine the truth of the matter. We must look briefly
at the questions which were raised, and the answers that were
obtained by Maupas and by others, for it will help us to un-
derstand the present state of the matter.

Maupas took a single individual (a Stylonychia), kept it
with plenty of food, and allowed it to multiply by repeated
division into two; he followed thus its history from generation
to generation. The creatures divided every eighteen hours or
so, and for about a hundred generations they remained strong
and healthy. Then sickly and deformed individuals began to
appear here and there; these became more and more numerous,
till finally all had degenerated thus; they died out completely

AGE, DEATH AND CONJUGATION . 259

at the end of five months, after 215 generations. Another
series, beginning with an animal that had just. conjugated, de-
generated and died at the end of 316 generations; and other
serles gave similar results.

Thus, said Maupas, it is clear that these creatures do get
old and die, just as higher animals do. The idea that they
are potentially immortal is a mistake; death inheres in the
process of life.

But why then are not these creatures all dead? How is it
that they exist at the present time?

The key to this is found, according to Maupas, and accord-
ing to the suggestions of many before him, in the process of
sexual union. As fertilization saves the life of the egg and
permits it to continue dividing for many generations, so does
eonjugation put new life into the dying infusorian, permitting
it also to continue multiplication for many generations. The
existence of sexual union in these creatures finds its explanation
in the fact that they, like ourselves, are mortal; and their
mortality is overcome, like our own, by the process of sexual
reproduction. Their lives begin with the strength of youth,
and inevitably run down the incline of age, as do our own.

But Maupas was one of those men who are not satisfied
with a brilliant hypothesis; if conjugation actually restores
vitality, he wanted to see it done. He allowed one of his
Stylonchias in the 156th generation to conjugate with another
that he captured wild. Then he took one from this pair and
allowed it to multiply. Most unfortunately he does not say
(doubtless he did not know) whether it was the old one or
the fresh one that he allowed to continue. But this creature,
which had conjugated, propagated itself for 316 generations
before it finally died of old age. Meanwhile, the rest of the
old stock, which had not been allowed to conjugate with fresh
individuals, died out in 59 generations.

Thus it appeared to be demonstrated that conjugation re-
stores vitality, that it rejuvenates. The brilliant hypothesis
had seemingly become the demonstrated reality.

260 HARVEY SOCIETY

But it is interesting to the student of the history of science,
and of scientific certainty, to discover that many years before
the time of Maupas the function and effect of conjugation had
been completely worked out in detail, by the most painstak-
ing investigations, so that in 1862 a statement for it could be
made that, according to the competent judgment of Engel-
mann, had been by a great abundance of observations raised
above all doubt.t. Yet this statement, though it seemed to
rest on irrefragable evidence, and agreed with everything else
that was known, was quite false, and in Maupas’s time had
been completely abandoned. Perhaps this was a type of the
fate to be met by many other supposed demonstrations as to
the function of conjugation, including that of Maupas—and
not impossibly the one here presented.

Before leaving the work of Maupas, we must mention cer-
tain other observations that he made which are of great im-
portance for understanding the matter. In his experiments,
after degeneration had begun, many specimens within the
same series (all derived from the same parent) conjugated
together. But this did not rejuvenate them. On the con-
trary they died all the sooner after conjugating with close
relatives. This happened in many eases.

So Maupas concluded (1) that conjugation with close rela-
tives does not rejuvenate; (2) that conjugation with related
individuals is not merely useless, but destructive; as soon as
they do this, says Maupas, their doom is sealed; (3) that re-
juvenation is due to conjugation with unrelated individuals.

This work of Maupas had of course tremendous influence;
it seemed to be definitive. There appeared to be no escape from
his conclusions, and for many years they were hardly seriously
questioned.

But in very recent times have come a series of investiga-
tions that have shaken the conclusions of Maupas and given
the entire matter a new aspect. It appears to me that the
time is ripe for a revision of judgment on the whole general

See Engelmann: Zeitschr. f. wiss. Zool., ii (1862), p. 347,

AGE, DEATH AND CONJUGATION 261

problem of age, death and conjugation in these lower organisms.
I shall attempt to give briefiy the grounds for such a revision,
and the direction which the final judgment must apparently
take.

1. The credit for seriously opening the question anew, as
well as for getting some of the most important evidence lead-
ing to what seem to me the correct conclusions, is due to Cal-
kins in his investigations extending from 1901 to 1904. After
cultivating Paramecium for about 200 generations (three
months) without conjugation, Calkins found that they become
depressed ; the division rate decreases; many die. Ag you re-
member, he found that by changing the diet at these periods,
by transferring from hay infusion to beef extract, to pancreas
or brain extract—the animals could be revived, and their life
and propagation continued. In this way he kept them for
742 generations (23 months), but at the end of that period
they finally died, in spite of any changes that were made in
their food. This showed that the infusoria could be kept alive
without conjugation a much longer time than Maupas had
observed. Calkins kept his animals for more than twice as
many generations as did Maupas.

The results of Calkins’s experiments can evidently be inter-
preted in two ways:

1. It may be held that the depression was due to a too
great uniformity in the food, or to the fact that the food and
other conditions were not fully adapted to the animals: what
the organisms needed was a change of diet. With frequent
changes in diet, perhaps, there would be no degeneration at
all. The final death would, on this interpretation, be due to
the fact that the injury produced by uniform diet had gone
too deep to be remedied by the means which Calkins tried.

2. But Calkins inclined, in view of the evidence then at
his command, to another interpretation. This work came
shortly after the first portions of Loeb’s brilliant investiga-
tions on artificial parthenogenesis. Calkins interpreted his
results in the light of those experiments. He held that the

262 HARVEY SOCIETY

infusoria were really in senile degeneration, ready to die of
old age. What he had done was essentially to induce artifi-
cial parthenogenesis; he had replaced conjugation by chemical
means. ‘The final death, he held, was due to the fact that
conjugation could not be indefinitely thus replaced; old age
finally asserted its power, and in the absence of conjugation
produced death.

Now I think it will be apparent at this point that there are
two independent questions involved in the investigations; to
understand later work it is needful to distinguish them clearly.

1. Does multiplication without conjugation result in degen-
eration, senility and death? What is the actual cause of the
degeneration that has been observed ?

2. Does conjugation remedy this degeneration? An affirma-
tive answer to this second question has been generally assumed.
If animals degenerate and die without conjugation, then evi-
dently conjugation must be what prevents and remedies this
result; such has been the reasoning. But if this is true it
must be possible to observe this effect of conjugation; we shall
do well to follow the example of Maupas, and not rest till a
plausible hypothesis has been transformed into an observed
fact.

These two questions then suggest two lines for further work,
and both of these lines have been followed.

Enriques and Woodruff have followed up the question:
What is the cause of the degeneration that has been observed ?
I myself have pursued mainly the second question, as to the
actual effects of conjugation. The results of all these investi-
gations seem to me harmonious and to lead to definite con-
clusions.

Enriques, in 1903 to 1908, carried out cultural investiga-
tions which led him to the following results and conclusions:

1. If he did not take pains to keep his cultures free from
the products of bacterial action, the animals degenerated in
time, just as observed by Maupas and Calkins.

2. But if he did keep them free from such products, by

AGE, DEATH AND CONJUGATION 263

changing the fluid every day or oftener, no degeneration took
place. He thus kept Glaucoma for 683 generations, without a
sign of degeneration, and similar results were reached with
other species.

Enriques concluded that the results of Maupas and Calkins
are explained by these observations. In their experiments, he
holds that the continued action of bacterial products was the
cause of the degeneration.

Every one with experience in such work must I believe agree
with Enriques that bacterial action is a most important fac-
tor in producing degeneration and death. But it seems clear
that he was in error in holding that this is the only cause.
The most significant feature of his results was the fact that
he kept his organisms more than twice as long as did Maupas,
with no degeneration whatever. He kept them for very nearly
the same number of generations as did Calkins, but in the
latter’s cultures there had been several crises of degeneration,
which finally ended in destruction. Enriques’ work indicated
strongly that this degeneration was not inevitable, though he
may not have explained with full adequacy why it occurs. En-
riques drew the general conclusion that there is no such thing
as senile degeneration in these organisms; they might enjoy
perpetual youth and live without end, if only the conditions
are kept healthful.

Then came the work of Woodruff, with which you are ac-
quainted ; work which appears to be definitive for the part of
the problem with which it deals. Woodruff investigated the
possibility that the degeneration observed by Maupas and Cal-
kins may have been due to too great uniformity in the cultural
conditions; or to the fact that the conditions employed lacked
something necessary to the continued health of the animals.

He therefore carried on a set of experiments wherein cer-
tain lines were subjected to frequent changes in condition,
while others were kept uniform. As you know, this gave the
key to the problem. At last accounts, the progeny of a sin-
gle individual were flourishing in generations subsequent to

264 HARVEY SOCIETY

the 2,500th, after four years and three months, without con-
jugation. They had been at that time kept for about four
times as many generations as had Calkins’s culture when it
died out, yet the animals in Woodruff’s experiment showed no
indication of degeneration. Later work by Woodruff seems
to show that if only the culture medium is properly selected,
no degeneration occurs even if the conditions are kept uni-
form.

The work of Woodruff demonstrates that the very lmited
periods within which Maupas and Calkins observed degenera-
tion has no significance for the question as to whether
degeneration is an inevitable result of continued reproduction
without conjugation. In other words, it annihilates all the
positive evidence for such degeneration, drawn from work on
the infusoria. It justifies the statement that the evidence is in
favor of the power of these organisms to live indefinitely, if
they are kept under healthful conditions. It shows that Weis-
mann was correct in what he meant by speaking of the poten-
tial immortality of these organisms.

Thus I believe that we may feel that one of our two main
questions has been definitely answered. Old age and death
have no necessary ‘place in the life of these creatures, even
without conjugation.

But this brings the second question back to us with greater
force than ever. What then is the effect of conjugation? What
role does it play in the life of these creatures. Are we wrong
in looking upon sexual union as a token of mortality?

This is the question to which I have addressed my own in-
vestigations, and with your permission I will speak next of
these.

Before taking up directly the effects of conjugation, I
would like to mention two subordinate points. First, in re-
gard to the question that we have just discussed. Five years
ago I started cultures from separate single individuals. Dur-
ing all that time there has been no opportunity for conjugation
with unrelated animals, such as Maupas held to be necessary

AGE, DEATH AND CONJUGATION 265

for continued hfe. Yet these cultures are still alive and
flourishing. Thus the progeny of a single individual may
certainly continue to multiply for five years without admixture
from outside. This then agrees with Woodruff’s results, save
that Woodruff knows that there has been no conjugation of
even related individuals in the line which he follows. But
Maupas found, as we saw, that conjugation among the progeny
of a single individual does not help, but is actually harmful;
if such individuals conjugated, their doom was sealed.

But is this result of Maupas generally true? Is inbreeding
among the progeny of a single individual injurious? Or did
Maupas’s animals die merely because they conjugated when
in a dying condition?

To test this point, I caused the progeny of a single indi-
vidual to conjugate together frequently. There was no evil
result whatever from this. To carry the process to an extreme,
I caused nine conjugations in succession within a single line,
each pair being in every case the progeny of one member of
the preceding pair. Thus the forefathers of the existing race
have gone through the process of conjugating together nine
times. Yet the progeny are as strong and well as ever.

It seems clear therefore that conjugation with close rela-
tives is not harmful in itself, in these creatures, though re-
peated many times. It is of course possible that there are dif-
ferences on this point among the infusoria, just as there ap-
pear to be among higher organisms. But it is certainly not a
principle of general validity that inbreeding is harmful.

But now we come to the main question. What difference
does conjugation make in the life of the race?

The way to test this question is to have a set of the animals
of the same parentage and history; to divide these into two
groups, and to allow one group to conjugate, the other not.
Then keeping the two groups under the same conditions, what
difference is found to be caused by the conjugation ?

In carrying out such experiments, the control set, those
that have not conjugated, are fully as necessary as the other;

266 HARVEY SOCIETY

otherwise we can not tell whether the phenomena shown by
those that have conjugated are really due to the conjugation
or not. Neglect to have this control set has led to erroneous
conclusions in some of the work previously done.

Comparative experiments of this character I have tried
many times with large numbers of individuals. As the ani-
mals begin to conjugate, they first come in contact and stick
together at the anterior end, though the process cannot be
consummated till the more posterior regions become united.
At this point then I intervened, separated the two before
union was complete, and removed each to a drop of water by
itself. Other pairs were allowed to complete conjugation, then
the members were isolated in the same way. The two sets
were then kept under the same conditions and their propaga-
tion was followed exactly. The two differ in no other respect
save that one set has conjugated, while the other has not.
What difference is caused by conjugation ?

1. We find that the animals which were ready to conju-
gate, which were actually attempting to do so, are by no means
in a depressed, degenerated condition, unable to multiply fur-
ther. On the contrary, if they are not allowed to conjugate,
each continues to multiply with undiminished vigor. Conju-
gation is then not necessary for further multiplication. And
we can by no means assume that because individuals are
ready to conjugate, they are therefore in a degenerate or se-
nile condition. Nor can we assume, as has been done by some
authors, that if the animals continue to multiply after con-
jugation, this shows that conjugation has had a rejuvenating
effect, for the same specimens continue equally without conju-
gation.

This fact, taken in connection with the results of Wood-
ruff, explains Maupas’s supposed positive evidence that con-
jugation produces rejuvenescence, as also the more recent re-
sults of Miss Cull.2 In Maupas’s ease, which is the one that

* Cull, Sara White: Rejuvenescence as a Result of Conjugation,
Journ, of Exper, Zool., 1907, 4, 85-89,

AGE, DEATH AND CONJUGATION 267

has been mainly relied upon as demonstrating rejuvenescence,
after the animals had become sickly (this being due, as Wood-
ruff’s work shows, to the fact that they had lived long under
conditions not fully adapted to them), he tried mating one
of them with a wild specimen. He then took one from this
pair, and found that it was strong and well, so that it multi-
plied for 316 generations. Maupas supposed that this was due
to the fact that conjugation had occurred. I believe it is
fairly clear that the result was not due to the conjugation, but
to the fact that he used a wild specimen, which had not been
living under unadapted conditions. He apparently used the
progeny of this wild individual for the remainder of his study.
Now, the results I have just described show that if he had not
allowed this animal to conjugate, it would have gone on mul-
tiplying just as well. Conjugation had nothing to do with
the result, the fact that the specimen came from natural con-
ditions is what counted.

Miss Cull’s evidence for rejuvenescence consisted in show-
ing that a considerable part of those that had conjugated con-
tinued thereafter to multiply. In the absence of the control
experiment, she did not discover that they continue equally
if they have not conjugated. There is then in this no evi-
dence for a rejuvenating effect of conjugation.

2. To return to my own investigations, the second important
result was to show that the specimens which have been allowed
to conjugate multiply much less rapidly than those which have
not conjugated. The difference is very marked, and showed
itself in every experiment of a great number. The multipli-
cation is slower, in those that have conjugated, for a month
or two after conjugation.

This result seems surprising, in view of the widespread im-
pression that multiplication becomes slower and slower, when
the animals are kept without conjugation, and that the fune-
tion of conjugation is to raise the vitality to the pitch where
multiplication may continue at the normal rate. It is there-
fore interesting to note that those sterling investigators, Mau-

268 HARVEY SOCIETY

pas and Richard Hertwig, knew well that conjugation does not
increase the rapidity of multiplication. Maupas emphasizes
and insists upon this fact again and again, at much length,
in opposition to the prevailing view that conjugation increases
the power of multiplication. What Maupas held was that con-
jugation saves the animals from death, though without increas-
ing their reproductive powers. Richard Hertwig observed,
correctly, that conjugation actually decreases the rate of mul-
tiplication.

3. A third result of comparing those that have conjugated
with those that have not is that many more of the former
die or are abnormal than of the latter. In a specially favor-
able experiment, out of 61 conjugants, eleven lines had died
out completely in 33 days, while of 59 lines that had not con-
jugated, but were otherwise similar, none had died in the
same period.

4. Usually a considerable number of the conjugants never
divide after conjugation, while all of those that have not con-
jugated continue dividing.

5. There is much greater variation among the progeny of
those that have conjugated than among those that have not.
This greater variation shows itself (1) in the rate of multi-
plication; (2) in dimensions. If we determine the coefficients
of variations, we find these much greater in the progeny of
those that have been allowed to conjugate.

Thus from these experiments, repeated many times, on an
extensive scale, there is no evidence that conjugation causes
rejuvenescence. On the contrary, it appears to be a danger-
ous ordeal, which sets back the rate of reproduction; and re-
sults for many individuals in abnormalities and death. What
conjugation seems to do positively is to produce a great num-
ber of varying combinations, some of which die out, while
others continue to exist.

Before attempting to draw more fully the conclusions from
these experiments, let us follow the investigations a little fur-
ther. In conducting an investigation it is necessary not only

AGE, DEATH AND CONJUGATION 269

to satisfy one’s self as to the correctness of a result, but also
to meet the objections of those that are firmly of the opposed
view. Now, to the results thus far set forth the following ob-
jections might be made. Conjugation, it could be said, may
indeed be of no use, and even disadvantageous, when organ-
isms are in a strong, healthy condition; they would doubtless
do as well without it. Probably they conjugate many times
when there is no necessity for it. Yet, it might be urged, if
you did not allow them to conjugate at all for many times the
usual period, then possibly the need of conjugation might
show itself. If you had a race that was in a depressed, de-
generate condition, from whatever cause, possibly you might
find that conjugation would restore them.

I therefore next carried out experiments to determine
whether this objection holds. <A certain race of Paramecium
conjugates as a rule every month or two. A culture of this
race was divided into two parts. One part was allowed to con-
jugate every month, while the other was cultivated on slides
and not permited to conjugate. In this way the one set was
allowed to conjugate four times in succession, in the course
of a number of months, while the other set did not conjugate
at all. We have thus a set that had missed four normal
conjugations.

Now, as a matter of fact, the set that had missed the con-
jugations did become depressed; it multiplied slowly and ir-
regularly, and many died. This may have been due, not to
lack of conjugation, but to long-continued cultivation on
slides; such cultivation does, of itself, produce an unhealthy
condition. But in any case, we have now a depressed race
and we can test the effect of conjugation upon it. Will con-
jugation end the depression, rejuvenate the organisms?

The experiment is performed by putting the members of
this depressed race under the conditions that induce conjuga-
tion. Then, as conjugation begins, we permit one set to com-
plete the process, while another lot is isolated without con-
jugation. The two sets are then cultivated under identical

270 HARVEY SOCIETY

conditions. We have now an opportunity to determine the
effects of conjugation on a depressed race, not complicated by
any other differing factors.

The results were striking, and to a certain degree unex-
pected. All those that had not conjugated continued to be
weak and sickly, and they died out completely in the course
of several weeks. Those that had conjugated showed great
variation (as usual); some died very quickly; others multi-
plied very slowly and finally died out; others multiplied more
vigorously than any of the non-conjugants. At the end of
six weeks, all those that had not conjugated were dead, while ©
certain lines of the others had multiphed and were numerous.
The difference between the two sets was in fact very striking.
But it is important not to misunderstand the nature of this
difference. The lot that had conjugated showed great varia-
tion, and many of the lines were not stronger than the non-
conjugants, dying out fully as quickly. But a few were
stronger, and these multiplied and replaced the rest. Thus
after some weeks, all the survivors had come from but three
or four among those that had conjugated.

But even in these the depressed condition had not been
completely overcome; they were still notably less vigorous than
the strain which had been kept throughout under more natural
conditions and had conjugated frequently.

Thus what had happened was this: Conjugation had pro-
duced much variation; some few of the variants had been more
vigorous and had lived, while the rest died.

This result when first reached was unexpected and difficult
to interpret. It seems of such importance that one felt it
necessary to try it again. J shall not describe to you the long
and wearisome process of providing anew the necessary con-
ditions and repeating the experiment. It will suffice to say that
the experiment was repeated and gave the same results as
before.

Thus I believe that we are in position to make certain posi-
tive statements as to the effect of conjugation. Conjugation

AGE, DEATH AND CONJUGATION 271

does not rejuvenate in any simple, direct way. What it does
is to produce variation; to produce a great number of different
combinations, having different properties. Some of these are
more vigorous, others less vigorous. The latter die, the for-
mer survive. This happens equally, whether the animals which
conjugate are at the beginning vigorous or weak. If they are
vigorous, then one of the most striking effects of conjugation is
to produce some lines that are less vigorous than the original
ones, so that they die out. If the animals which enter conjuga-
tion are weak, then one of the most striking effects of conjuga-
tion is to produce certain combinations that are more vigorous
than the original ones, so that they survive, while those that
did not conjugate die out. In a short time the entire race is
replaced by the descendants of a few of those that conjugated.

Now, the relation of all this to certain things that are
known in higher organisms seems fairly clear. In higher ani-
mals likewise the result of intercrossing is to produce varia-
tion. We don’t call it variation nowadays, because we know
something more about it; we call it Mendelian inheritance.
In the crossing of two individuals that resemble each other ex-
ternally, progeny of many different kinds are produced. In
crossing white and cream-colored four o’clocks Correns got
eleven kinds of red, white, yellow, and striped offspring among
the grandchildren. Heredity, as the Mendelian analysis has
revealed it to us, is a process of producing a great number of
diverse combinations by the varied intermingling of the char-
acteristics (concealed or apparent) of two indivduals.

Now, it seems clear that this is exactly what is done in the
conjugation of the infusoria. We have not yet succeeded in
determining the precise rules of recombination, such as have
been worked out for many eases in higher organisms; so that
for the infusorian we are as yet limited to the statement that
conjugation produces variation.

Thus the conjugants apparently have the same relation to
each other, so far as inheritance is concerned, as do sperm and
egg in the higher organisms. We ought to find that the

272 HARVEY SOCIETY

progeny inherit from both of the conjugants. What are the
positively known facts as to this?

Regarding biparental inheritance in these lower animals, we
are as yet in that relatively backward stage of science that is
implied by the necessity for the use of statistical methods.

We hear at times the Kantian dictum that any subject is
scientific only to the extent that it makes use of mathematics.
This dictum is sometimes put before us as an argument for
using statistical methods. But for these we could almost re-
verse the statement, and say that any subject is scientific only
to the extent that it can dispense with statistical methods.
These are necessary mainly when we cannot understand and
control the separate causes that are at work; as soon as we
can do this such methods become largely unnecessary.

But the use of statistical methods enables us to show that
in conjugation the progeny inherit from both parents. By
working out for the rate of fission the coefficient of correlation
between the descendants of the two that have conjugated, we
find that they have nearly the same closeness of relationship
as brothers and sisters; and somewhat closer than cousins. The
coefficient of correlation is about .4. This means that if the
progeny of one member of a pair have a peculiarity, the
progeny of the other member have the same peculiarity, though
in a less degree, and this similarity can apparently come only
through inheritance from both parents.

Comparing conjugation with the fertilization of higher ani-
mals, we find then this state of the case. In higher animals
fertilization has two diverse effects, which recent investigation,
particularly that of Loeb and his associates, has clearly disen-
tangled: (1) On the one hand, it initiates development; it
prevents the egg from dying, as it would do if not fertilized.
This function of fertilization is the one that is replaced by the
processes which induce artificial parthenogenesis. (2) But,
secondly, fertilization brings about in some way inheritance
from two parents. When there is inheritance from but one
parent, the inheritance is as it were complete; the child as a

AGE, DEATH AND CONJUGATION 273

rule resembles its parent in all hereditary characteristics; this
is the result of the so-called ‘‘pure line’’ work. But when
we have biparental imheritance, a great number of different
combinations of the characteristics of the two parents are pro-
duced, so that the process of fertilization is one that in this
respect completely alters the face of organic nature, producing
infinite variety in place of relative uniformity.

These two functions of fertilization, the initiation of de-
velopment, on the one hand, the production of inheritance
from two parents, on the other, are logically independent;
they might conceivably be performed at different times and
by different mechanisms. The fact that in many organisms the
’ same mechanism that brings about biparental inheritance is
likewise the one that initiates development might from certain
points of view be called an adaptation. Its result is to insure
that in all the organisms that develop there shall be inheritance
from two parents, not from one. In the work on artificial
parthenogenesis these two functions have been separated ex-
perimentally ; the initiation of development takes place alone.

Now, in endeavoring to understand conjugation, attention
has been given hitherto almost exclusively to the first of these
two functions. It was held that the function of conjugation
must be to make possible life and development where it was
otherwise impossible, just as fertilization arouses the egg to
further life and development. But it turns out that conjuga-
tion, instead of having this one of the two functions of fertili-
zation, has the other. The two functions are in the infusorian
separated, just as they are in artificial parthenogenesis, but
it is the second, not the first, that we have before us. Conju-
gation is not necessary in order that life and reproduction
shall continue; they continue without it.

But the life which thus continues is uniform and unchang-
ing. To give biparental inheritance, with varying mixtures
of the characteristics of the two parents; to produce these new
combinations in great variety, conjugation is necessary. And
when this happens under such conditions that the original

Q74 HARVEY SOCIETY

combinations were not adapted to survival, then some of the
new combinations produced often are adapted to the condi-
tions; conjugation then results in a survival of an organism
that would have been completely destroyed without it. It is
most interesting in this connection to observe that conjugation
is usually induced by an unfavorable change of conditions, a
change of such a nature that the organisms begin to decline.
Thereupon conjugation occurs, so that new combinations are
produced, adapted to varied conditions, some of which may
survive.

Thus it appears to me that the whole series of investigations
on old age and on conjugation leads to a unified result, and
one that is in most respects in consonance with what we ob-
serve in higher animals. But in one respect there is a differ-
ence, and this brings us back to the question with which we
began. Is death a necessary accompaniment of life? Do the
life processes necessarily take such a course that they must
lead to death?

To this question the work on the infusoria answers No!
The evidence that was supposed to show that the life processes
must gradually run down and end in death had been shown
by the work of Woodruff not to lead to any such conclusion.
Woodruff appears to be clearly justified in his recent state-
ment that these organisms ‘‘ have the potentiality to perpetu-—
ate themselves indefinitely by division,’? and my own studies
on the effects of conjugation furnish the complement to this
result, agreeing with it fundamentally.

All that Weismann meant by saying that such creatures
are potentially immortal has shown itself correct. Death is not
necessarily involved in life.

But why, then, in higher animals and in ourselves, even
when there is no accident and conditions are good, do we find
death coming as a natural end to life? Why should there be
this tremendous difference in such an essential point between
the lower organisms and the higher ones? Is there any possi-
bility of mistake as to the necessity in the case of higher
organisms ?

AGE, DEATH AND CONJUGATION 275

To find a ground for this difference, we shall do well to fol-
low the usual procedure in science, and examine other differ-
ences between these lower creatures and the higher ones, to
see if these may not give us the clue. And here I touch upon
a matter that had been fully developed by Minot and others;
it is worth while to speak of it briefly, because work bearing
upon the matter has recently appeared.

The most striking other difference between these lower or-
ganisms and the higher ones is evidently the fact that in the
higher organisms the body becomes large, complex and differ-
entiated into a number of diverse parts; different cells of the
body have taken on themselves different functions and different
structures. This appears to involve a correlative loss of the
power of carrying on the fundamental vital processes; the
cell that has become filled with lime, or that has transformed
into muscle, no longer retains the vital elasticity of the cell
in which the diverse functions remain well balanced. Products
of metabolism are no longer perfectly removed; other processes
necessary to life become clogged. The final result of this is a
complete cessation of the processes; age and death follow upon
differentiation. This, as you know, is the theory of Minot.
According to it, the welfare of the individual cell is as it were
sacrificed to that of the body as a whole, and this in turn in-
volves the final destruction of the body itself, so that a period
of higher diversified life is purchased at the price of ultimate
death.

Minot has added to this fundamental idea certain views as
to quantitative relations of nuclear and cytoplasmic material
in the cell. Relative increase of cytoplasm is taken to be the
beginning of the process of aging, while relative increase in
nuclear material is considered a process of rejuvenation. Such
rejuvenation was held therefore to occur in the early cleavage
of the egg, since here the amount of nuclear material was sup-
posed to increase greatly in proportion to the amount of
cytoplasm.

The recent important paper of Conklin has shown that in

276 HARVEY SOCIETY

the cleavage of many animals this increase of nuclear ma-
terial relative to the cytoplasm does not occur. Conklin’s re-
sults will apparently go far in rendering untenable or modify-
ing all theories in which great significance is attached to the
precise quantitative relations between nucleus and cytoplasm.
But what is important to realize is that this has no bearing
on the fundamental feature of the theory that aging and death
are due to differentiation. The grafting of the theory that the
quantitative relation between nuclear and cytoplasmic material
is an essential point upon this general theory was unfortunate
from the beginning.

Everything points, it appears to me, to the essential correct-
ness of the view which holds age and death to be the result
of the greatly increased differentiation of larger organisms.
Is there then any probability that we shall some time find that
in the higher animals, as in the lower ones, death need not
occur ?

Evidently not. If death is the price of differentiation, then
after the goods have been delivered the price must be paid.
To prevent a higher organism from undergoing death would
at the same time prevent him from becoming a higher organ-
ism. And the cell which remains in the embryonic condition—
the cell of the germ glands—is even now as immortal as the
cell of the infusorian. Death, as Minot says, is the price we

pay for our more complex life. Age and death, though not
inherent in life itself, are inherent in the ‘diterenaaias which
makes life worth living.

ON MALARIAL FEVER, WITH SPECIAL
REFERENCE TO PROPHYLAXIS *

WILLIAM SYDNEY THAYER, M.D., F.R.C.P.I.
Johns Hopkins University, Baltimore

T is now over thirty years since that patient and careful
student Laveran discovered parasites in the blood of suf-
ferers from malarial fever, and recognized their significance ; it
is over twenty-five years since Golgi pointed out the relations
between the life history of the parasites in their human host
and the manifestations of the malady; it is nearly fifteen years
since Ross’s discovery of the development of the microdrganisms
in the body of the mosquito, which, along with the studies of the
Italian school, revealed the manner in which the disease is
spread and the way in which infection takes place. In the ten
or twelve years which have followed these discoveries, the ad-
vanees in our knowledge of the wxtiology, prophylaxis, and treat-
ment of various other infectious diseases, such as yellow fever,
cerebro-spinal meningitis, syphilis, poliomyelitis, have been so
rapid and so absorbing, that here in America, at least, the
lessons which we have learned with regard to the nature of
malarial fevers and the methods of prophylaxis and treatment
by which they may be controlled, have not been taken to heart
as they have been in some other parts of the world.

A brief consideration, therefore, of the present state of our
knowledge concerning malaria, and of some of the problems
which concern us, as a profession and as a people, with regard
to questions of prophylaxis and treatment, may be worthy of
consideration before this society.

* Delivered March 23, 1912.

278 HARVEY SOCIETY

ARTIOLOGY. NATURE OF INFECTIOUS AGENT.
MANNER OF INFECTION

The infectious agent we now know to be a sporozoon of the
order Hemosporidia, sub-order, Acystosporea, genus, Plas-
modium.

These hemosporidia have two cycles of existence—one, asex-
ual (schizogonia), takes place in the blood of vertebrates; the
second, sexual (sporogonia), in the viscera of certain insects.
The vertebrates appear to represent the intermediate hosts, the
insects the definitive hosts. In the case of Plasmodium, the de-
finitive hosts are various mosquitoes belonging to the sub-
family Anopheline.

The genus Plasmodium is represented by three distinct
species, differing not only in their morphological and biological
characteristics but in the character of the manifestations to
which they give rise in the infected individual. These species
are:

Plasmodium vivax (Grassi and Feletti, 1890), the parasite
of tertian fever.

Plasmodium malarie (Laveran, 1881), the parasite of
quartan fever.

Plasmodium falciparum (Welch, 1897), the parasite of
eestivo-autumnal or tropical fever.

In the human being, the parasite passes through its asexual
cycle (schizogonia) in the substance of the red blood-corpuscle,
dividing, at maturity, by segmentation, into a fresh brood of
young parasites, merozoites, which in turn attack new corpus-
cles, and pursue again their cycle of existence, a process which
may be continued for an indefinite period of time. Alongside
of the parasites pursuing this asexual cycle of development,
there appear, however, in most cases, other organisms—dis-
tinguishable, in the younger tertian and quartan parasites,
mainly by differences in their nuclear structure, but in the
estivo-autumnal parasite, by gross differences of form—which
early begin to take on sexual characters. These gametocytes
show, in all forms of malaria, a resistance to quinine, greater
than members of the asexual cycle, but slightly greater in P.
vivax and P. malarie, very markedly so in Plasmodium
falciparum.

MALARIAL FEVER 279

Immediately after the removal of the parasites from the
human host by the anopheline mosquito, actively motile fila-
ments (microgametes) escape from the male element (micro-
gametocytes) and penetrate the female organism. The fecun-
dated female element (odkinete) develops then the power of
active locomotion, penetrates the wall of the stomach of the
mosquito, and there becomes an odcyst, from which, after about
eight days, at maturity, escapes a brood of newly formed
sporozoites (sporonts) which collect in the salivary glands of
the mosquito, from which they are discharged into the succeed-
ing human host.

On entering the blood of the human being, the sporont
attacks a red blood-corpuscle, enters it, and thenceforth becomes
indistinguishable from the product of asexual division
(schizont). In the red blood-corpuscle it enters immediately
upon the ordinary cycle of asexual development (schizogonia).
The length of the sexual cycle of development in the mosquito
host depends upon the conditions under which the insect is
placed, amounting, under favorable circumstances, to about
eight days.

The anophelines which may act as definitive hosts for the
parasite belong to several genera and a variety of species. In
the United States, two genera and eight species have been
recognized, namely: Anopheles punctipennis (Say) ; Anopheles
pseudopunctipennis (Theobald) ; Anopheles crucians (Wiede-
mann); Anopheles occidentalis (Dyar and Knab) ; Anopheles
atropos (Dyar and Knab); Anopheles walkeri (Theobald) ;
Anopheles maculipennis (Meigen); Calodiazesis barbert
(Coquillet).

In Panama, the commonest hosts of the malarial parasite
are: Anopheles albimanus and Anopheles tarsimaculata
Anopheles pseudopunctipennis is apparently but slightly con-
cerned in the transmission of malaria, and it has not yet been
proven that Anopheles malefactor transmits the disease.*

*Darling: Transmission of Malarial Fever in the Canal Zone by
Anopheles Mosquitoes. J. Am. Med. Ass., Chicago, 1909, liii,
2051-2052.

280 HARVEY SOCIETY

It is a question whether, in the temperate parts of this
country, the common Anopheles punctipennis plays any part in
the transmission of malaria, and in temperate Europe and in
America the main agent of transmission is Anopheles macult-
penms.

The anophelines are essentially country mosquitoes, breeding
by preference in shallow pools, especially those containing a
growth of alge; they rarely develop in water standing in tubs
or about houses as do Culices, the common house mosquitoes
of the city. Several species, however, breed in marshes with
brackish water. The anophelines are, as a rule, night-biting
mosquitoes, that is, they bite only at night or at dusk, morning
or evening. In daytime, they retire to dark places, behind
curtains or clothes or even into holes in the ground. This has
led to the construction of rather interesting mosquito traps.
The simplest of these are boxes lined with black or dark blue
cloth. The mosquitoes seek the dark recesses and are suddenly
shut in by a lid—and later destroyed. Blin,? who noticed that
mosquitoes often repaired to crab holes by day, dug small
holes in the ground about 16 inches deep at an acute angle
to the surface. The holes, protected from direct light, are soon
filled with mosquitoes which are burned by torches.

The odcysts will not develop in their mosquito host at all
temperatures and under all conditions; they grow best at a
temperature from 20° to 30° C. They are killed in tem-
peratures steadily under 16°. Exposure, however, to a temper-
ature as low as 10° or 13° for an hour will not kill the odcyst
if the insect later be placed under favorable surroundings.
Anopheline may bite at a season considerably earlier or later
than that. which is suitable for the complete development of
oocysts (Janesd)*.

* Blin: Destruction des moustiques par le procédé des trous-piéges.
Caducée, Par., 1909, ix, 163.

* Janes6: Der Einfluss der Temperatur auf die geschlechtliche Gen-
erationsentwickelung der Malariaparasiten und auf die experi-
mentelle Malariaerkrankung. Centralbl. f. Bakt., ete., I Abt.,
Orig., 1905, xxxviii, 650.

MALARIAL FEVER 281

The parasite is not transmitted to the offspring of the
mosquito. The average length of life of the anopheline mos-
quito is difficult to determine. Artificially cultivated, they have
been kept alive for 56 days.* Ross calculates that the average
natural life of an anopheline is of about three weeks’ duration.
During the cold weather, a certain number of adults, especially
females, hibernate in lofts, cellars or dark rooms, coming out
again with the return of warm weather. The length of time
during which a mosquito may contain viable sporozoites in the
salivary glands cannot be stated with positive certainty. The
observations of Jancsé above mentioned would tend to suggest
that in temperate climates few mosquitoes can be infectious at
the beginning of the succeeding season.

Among mosquitoes collected at the beginning of the malarial
season, the number of infected insects is extremely small. It
cannot, then, be regarded as proven that the hibernating mos-
quito may be a carrier of infection.

SEASONAL INCIDENCE OF MALARIA; RELAPSES ; LATENT INFECTIONS

Relapses——Although the infection of a human being can
occur only as a result of a bite by an infected mosquito, yet the
curve of seasonal prevalence of the disease is remarkably mod-
ified by the fact that relapses, which are apparently commonest
in tertian malaria, have a definite seasonal relation, being espe-
cially frequent in all climates at the onset of warm weather in
spring, and notably preceding the appearance -of anophelines,
which initiates the annual epidemic.

The seasonal occurrence of malaria in Baltimore, which
corresponds very closely with the figures reported by the
observers in Rome, may be illustrated by the following table:

EEE

‘Nuttall and Shipley: Studies in Relation to Malaria—The Structure
and Biology of Anopheles (Anopheles maculipennis). J. Hygiene,
Cambridge, 1902, ii, 58-84.

282 HARVEY SOCIETY

SEASONAL DISTRIBUTION OF MALARIA IN BALTIMORE

s| 8/8) 2] e) 2] 8) ale!8] 8] rota

A)e (S| 215121 2|2\ 8/8) 2 tales

mRertiane) oe cece 12 | 12 | 28 | 51 | 76 | 68 |1381)161/153/168) 54 i 931
Quartans.- ee Sle Ee COM tH CO] MACON eas OH AM aM eh 17
Astivo-autumnal| 5] 1] 2} 5] 2] 3] 37} 99/191/203) 63 fe 633
Combined....... OF ea ON iOS el: 3] 3) 4) 1 ow2 32

20 | 15 | 31 | 57 | 78 | 72 |174/263/350/383|127| 43 | 1613

It was further found on questioning these patients, who, for
the most part, were ordinary ward patients, people who might
well have forgotten a previous malarial attack, that about two-
thirds of the individuals who had consulted us during the first
half year had had previous attacks, and might therefore be
suffering from a relapse, while only about one-third of those
suffering with malaria during the second half year could
remember a preceding affection of the same sort.

It would thus appear that the greater part, if, indeed, not
all of the cases occurring early in the season in temperate
climates, are relapses from previous attacks.

The causes of relapses have been much discussed. Un-
treated malaria often disappears spontaneously, but these dis-
appearances are usually followed by recrudescences and re-
lapses at varying intervals through months and years. Caccini ®
finds that in tertian fever, relapses and rallies alternate in
periods of from two to three weeks. In exstivo-autumnal fever,
the relapses and rallies in untreated cases occur at rather
shorter intervals, amounting usually, according to Carducci,®
to about seven days. Often, however, spontaneous recoveries
may occur, particularly in tertian fever, followed by relapses
after intervals of months or indeed even years. The condition
here is indistinguishable from that which occurs after more or

*Caccini: Duration of the Lateney of Malaria after Primary
Infection, ete. J. Trop. Med., Lond., 1902, v, 119; 1387; 159; 172;
186.

* Carducci (A.): Sulla cura e sulla causa delle recidive nella malaria.
Atti d. Soe. per gli stud. d. malaria, Roma, 1905, vi, 27.

MALARIAL FEVER 283

less incomplete treatment by quinine. From a seasonal stand-
point, as has been said, relapses occur with beginning warm
weather, or, in the tropics, after the onset of the rainy season ;
but in any individual with latent malarial infection and some-
times after it has apparently been eradicated by long continued
and careful treatment, a relapse may occur following sudden
changes of climate, exposure, fatigue, emotional excitement,
or infectious disease.

The cause of such relapses is still uncertain. No evidence
exists in support of the old assumption that the parasite per-
sists somewhere in the organism in the shape of encapsulated
spores. Ross? believes that it is, on the whole, more probable
that certain more resistant parasites of the asexual cycle may
persist for very long periods of time, in numbers so small as to
produce no definite symptoms, but ever ready to multiply under
circumstances which lower the resistance of their hosts,

Bignami § is inclined to believe that the persistent relapses
in some cases may be due to the acquisition, by certain strains
of the parasites, of a tolerance for quinine such as has been
observed, for instance, in the case of trypanosomes toward prep-
arations of arsenic.

Others have suggested, however, as a possible cause of re-
lapses, the parthenogenetic sporulation of the more resistant
gametocytes. Grassi,? Schaudinn,’® and others describe pictures
which they interpret as a parthenogenetic sporulation of macro-
gametes. It is well known that gametocytes are more resistant
against treatment with quinine than organisms of the asexual
eyele, and it is suggested by these observers that the partheno-
genetic sporulation of macrogametes which have persisted for a
long time after treatment may well be the cause of the reawak-

"Ross: The Prevention of Malaria. 8° London (Murray), 1910, 115.

*Bignami: Sulla patogenesi delle recidive nelle febbre malariche.
Riv. ospedal., Roma, 1911, i, 305-317.

> Grassi (B.): Die Malaria. Studien eines Zodlogen. 2 ed., Jena,
1901.

® Schaudinn (F.): Studien iiber krankheitserregende Protozoen. II,
Plasmodium Vivax, ete. Arbeit. a. d. K. Gesndhtsamt., 1903, xix,
169.

284 HARVEY SOCIETY

ening of latent infections. Similar pictures of segmentation in
crescents were described many years ago by Canalis. This
process, though apparently confirmed by good observers, is still
doubted by a student so reliable as Bignami.”

Craig** contends that these so-called parthenogenetic
sporulating forms are, in reality, more resistant elements, re-
sulting from the early conjugation of two young parasites.
This conjugation, first described by Mannaberg,’* who, as is
well known, has long believed that it is a regular step in the
formation of crescents, and Ewing in young forms of the
tertian parasite, has been repeatedly observed by Craig, who
regards the resultant zygote as a more resistant body destined
to remain in the human organism after other forms of parasite
have disappeared as the result of treatment or of the natural
destructive powers of the blood. It is to the reawakening and
segmentation of such bodies, he believes, that the relapses are
due.

Mary Rowley-Lawson *° has recently described and pictured
that which suggests a process of impregnation of macrogametes
within the body of the human host in exstivo-autumnal infec-
tions, and has apparently followed every intermediate stage
from impregnation to segmentation (schizogonia). Such a
diversion of the usual process of development might well
account for some relapses. The recent remarkable studies of
Bass,’7 who asserts that he has succeeded in cultivating the

“Canalis (P.): Studi sull’ infezione malariea, ete. Arch. per le se.
med., Torino, 1890, xiv, 73.
* Bignami: op. cit.
* Craig (C. F.) : Intracorpuseular Conjugation in the Malarial Parasite
and its Significance. Am. Med., Phila., 1905, x, 982; 1029.
“Mannaberg (J.): Beitriige z. Kenntniss der Malariaparasiten.
Verhandl. d. Cong. f. innere Med., Wiesb., 1892, xi, 437-449.

* Ewing (J.): On a Form of Conjugation of the Malarial Parasite. J.
Hopkins Hosp. Bull., 1900, xi, 94. Also, Malarial Parasitology.
J. Exper. M., N. Y., 1901, v, 475.

* Rowley-Lawson: The A‘stivo-autumnal Parasite, ete. J. Exper.
M., N. Y., 1911, xiii, 263-289.

“Bass (C. C.) : A New Conception of Immunity, ete. J. Am. M. Ass.,
Chicago, 1911, Ivii, 1534.

MALARIAL FEVER 285

malarial parasites outside the human body, should, if con-
firmed and extended, shed a flood of light upon the develop-
ment of the organism.

However this may be, the malarial season in all countries
is almost invariably preceded by an outbreak of relapses. These
relapses, at the beginning, occur at a time when the anophelines
are not yet active. The true epidemic follows shortly after the
appearance of anophelines. But it is not necessary that there
should be an active outbreak of relapses, for it has been shown
that latent malaria is by no means uncommon. This was
brought out especially by Koch** in his malaria expedition to
the East. Koch called attention particularly to the fact, which
has been confirmed by many other observers in all parts of the
world since that time, that in malarious localities the proportion
of children who are infected is very large, but more than this,
a large proportion of these children carry the infection without
signs so striking as to be recognized by the ordinary individual.
It is not an uncommon thing for a child to be playing about,
apparently in reasonably good condition, with active parasites
demonstrable in the circulation.

But children are not the only malaria carriers, and the
number of adults who may keep at work with considerable
numbers of malarial parasites, especially of sstivo-autumnal
gametocytes, in the-blood is, in malarious districts, very large.
For instance, in the Panama Canal Zone, where so much has
been done, Darling,’® a few years ago, reported that in several

“Koch (R.): Erster Bericht iiber die Thiatigkeit der Malariaexpedi-
tion. Deutsche med. Wehnschr., 1899, xxv, 601. Zweiter Bericht
iiber die Thiatigkeit der Malariaexpedition. Ibid., 1900, xxvi, 88.
Dritter Bericht tiber die Thitigkeit der Malariaexpedition. Ibid.,
1900, xxvi, 296. Vierter Bericht iiber die Thatigkeit der Malaria-
expedition. Ibid., 1900, xxvi, 397. Fiinfter Bericht iiber die
Thiatigkeit der Malariaexpedition. Ibid., 1900, xxvi, 541. Schluss-
bericht iiber die Thatigkeit der Malariaexpedition des geh. med.
Raths. Prof. Dr. Koch. Deutsche med. Wehnsehr., 1900, xxvi,
733. Zusammenfassende Darstellung der Ergebnisse der Malaria-
expedition. Deutsche med. Wehnschr., 1900, xxvi, 781; 801.

* Darling: op. cit.

286 HARVEY SOCIETY

regions where the malarial sick rate did not fall to zero and
where no anophelines were breeding, 10 per cent. of the men
who were at work without symptoms had parasites in the blood.
Thirty per cent. of these were xstivo-autumnal, 70 per cent.
tertian. Among the Spanish and West Indian families, the
latent malarias amounted to 30 per cent. Darling observes:
“Tt is this latent malaria in every tropical community that con-
tributes largely to the preservation of malarial parasites, and
to the infection of anopheles when, after the rainy season,
mosquitoes have begun to breed in numbers.’’

Craig,?° who had previously made important observations
tending to show that the proportion of malarial carriers among
adults is nearly as high as that among children, has recently
brought together in one table the observations as to latent
malaria made by a variety of observers in different parts
of the world (Koch, New Guinea; Thomas, Mafios, North Brazil ;
Annett, Dutton and Elliott, Nigeria, Africa; Craig, Philip-
pines; Ollwig, Dutch, East Africa; Panse, Tongo, East Africa;
Sergent, Algeria; Plehn, Kameruns, W. Africa.

TABLE I (From Craig).

PREVALENCE OF LATENT INFECTION AT Various AGEs.
CoNSOLIDATED TABLE.

Age. No. Examined. | No. Infected. cs bios
TAO ON RATS 7s bot eee Sete 1684 502 29.8
Oi toOlvearss)2). fae ones see 1645 463 28.1
TO to 1G years 6.0 feck ees ae 1390 437 31.4
V0 ET 1 ae eu AeA 4931 1139 23.
TOUS. conan G ae oes 9650 2541 26.3

These figures appear to indicate that there is no great differ-
ence between the number of malarial carriers among children
and adults.

” Craig: Important Factors in the Prophylaxis of the Malarial
Fevers. Southern M. J., Nashville and Mobile, 1912, v, 50-57.

MALARIAL FEVER 287

Craig estimates that about 50 per cent. of latent cases are
gamete carriers. The existence of these latent infections,
especially among individuals who have lived long in infected
districts, is generally regarded as evidence of a certain
acquired immunity. But the fact that parasites are to be dis-
covered in the blood opens the question as to how far the
immunity is to the parasite or to its toxic products. Some have
assumed that the latter alone is the case, and true it is that the
number of parasites found in these individuals is sometimes
no less, apparently, than that associated in other instances with
severe symptoms. On the other hand, the number is usually
rather small, and the immunity may well consist, in part at
least, in the power of the organism to destroy the parasites so
as to keep them always at a minimum below that necessary to
produce symptoms. Although all efforts artificially to pro-
duce immunity have failed, yet there would seem to be a certain
acquired immunity in some individuals who have lived long
in malarious regions.

TREATMENT AND PROPHYLACTIC METHODS

From this summary of our knowledge concerning the nature
and manner of spread of malarial fever, it is quite clear that
the prevention of the malady is possible, theoretically, by
breaking the chain of existence of the infectious agent at any
point in its cycle in mosquito or in man, Abundant proof of
this proposition has been afforded by a series of practical
experiments.

1. Various Italian *? and English 2? observers have shown

that thoroughly carried out mechanical protection against the
bites of mosquitoes will permit individuals to remain for in-

™ Crassi: op. cit.
Di Mattei. La profilassi della malaria colla protezione dell’ uomo
dalle Zanzare. Atti d. Soe. per gli stud. d. malaria. Roma, 1901,
ii, 24-32.
*Sambon and Low: British Med. Jour., Lond., 1900, ii, 1679.

288 HARVEY SOCIETY

definite periods in regions where the infection is extremely
prevalent.

2. Ross ** and others in Ismailia, Port Said, and elsewhere
have shown that by thorough drainage and removal of the
breeding places of anophelines, together with measures such as
oiling the surface of pools which cannot be drained, the de-
velopment of the larve may be prevented and the mosquitoes
thus entirely removed from certain localities. And this results,
as might be expected, in the immediate disappearance of the
disease.

3. Koch and his students ** in New Guinea and elsewhere
have further shown that by carefully seeking out the relapses
before the outbreak of the malarial season and by thorough
treatment of these, together with any new cases that may break
out, the parasites may be so far destroyed in their
human hosts that when the season characterized by the prey-
alence of anophelines comes on, the malarial epidemic re-
mains absent.

With these practical demonstrations, why, then, is not the
eradication of malaria an easy problem? Why have we not
taken our malaria in hand as we have yellow fever? Why can
we not, by isolating and thoroughly treating infected individ-
uals, while protecting them from the bites of mosquitoes—why
can we not by these methods easily eradicate the disease?

The reasons are obvious. The mildness of the manifestations
in many eases, the frequency of latent infections, the length
of time during which treatment and precautions must be con-
tinued, make it very difficult to carry out such measures ex-

*Ross: The Prevention of Malaria. 8°, London (Murray), 1910,

496 et seq.
“Koch (R:): Berichte iiber die Thitigkeit der Malariaexpedition.
Op. cit. «

Frosch, P.: Die malaria bekimpfung in Brioni (Istrien). Ztsehr. f.
Hyg. u. Infectionskrankh., Leipz., 1903, xliii, 5-66.

Schilling: In Ross: The Prevention of Malaria, 8°, London (Mur-
ray), 1910, 496 et seq.

MALARIAL FEVER 289

cepting in small communities and under practically military
surveillance.

There have been ardent partisans of each individual method
of prophylaxis, and many interesting experiments on larger
or smaller scales have been carried out. From these experi-
ences several conclusions may definitely be drawn:

1. The methods by which malaria may be attacked, may be
divided into: (a) individual prophylaxis—that relating to the
patient himself; (b) public prophylaxis—those general meas-
ures for the protection of the inhabitants which should be
adopted by countries, states, counties, cities, and towns.

2. There is no one sovereign method of malarial prophy-
laxis. Different methods vary in their applicability according
to the physical geography and climate of the locality, according
to the denseness and nature of the population, and according to
the form of government.

At the base of the prophylaxis of malaria, in a civilized
country, stands the individual practitioner. If every prac-
titioner of medicine should recognize and treat thoroughly every
ease of malaria that came to him, and should take precautions
so that relapses might early be recognized and treated in their
turn; if, in other words, each practitioner sterilized each in-
dividual patient, much of the work would be done.

What does thorough treatment mean? How are we to
recognize the early relapses and the latent cases of malaria?

Much of the prevalence of malaria depends upon insuffi-
cient and incomplete treatment of the disease, and the very
brilliancy of the specific action of quinine is indirectly the
cause of much carelessness in treatment, based upon the lack
of general knowledge as to the best method of giving the
drug and as to its effect upon the parasites.

Different salts of quinine vary greatly in their solubility
in water, with regard to which also the statements of different
authors vary extraordinarily. The following table compiled
from several works will give some idea as to these points:

290 HARVEY SOCIETY

TaBLE SHOWING EQUIVALENTS OF QUININE, SOLUBILITY, AND RATE OF
ELIMINATION OF DIFFERENT SALTS OF QUININE.

Salt. Sfguiaine, | Solubility. | APpymnee
Per cent. Minutes.

Birhydrochlorate. 2. (eee eee ts soit 72.0 1/1
Hydrochlorates=sar.e eon ea 81.8 1/40 15
igdrobromatess 225i pec dotils ak uae 76.6 1/45
Bihydrobromatesic. sce eos a ce 60.0 1/7
AMectate-s:: Act chet Seti wie eS 84.0 30
Gee TR IE iia Nt eee a 67.0 1/820 30
Bisalphated.omenecert este ere ke 59.1 1/11 30
SUIpbate sks Mae ice oe cic TE 1/800 45
AAR O ond OAs aed Sale c\m olacetsee Se ots 20.0 slight 180
UGG eo oreo oto Ree atte 81.0 1/12,500
PPR OSPNRGS 32 5,51215-4, fio, Melon e evcis ele 76.2 1/420
WAIGHIAR ATC ste ha caine cine aioe «oes 73.0 1/120°
MEA CEALC yates Gusts bate Sire ee ee eee 78.2 1/110
DAHEVIRGE. cies eicise es ue Sue eee aie 70.1 1/225
INTROTHALE. oie harem ces ee ai eh eae 69.4 very slight

The rapidity and completeness of absorption of quinine
vary greatly according (1) to the salt used; (2) to the form in
which it is administered; (3) to the method in which it is intro-
duced into the body. Most quinine (MacGilchrist)** is absorbed
by the small intestine; a very small amount by. the stomach,
when the drug is introduced during fasting and in an easily
soluble form; and a relatively smaller amount yet from the
large intestine. The absorption is somewhat retarded when
quinine is given with or after food, and also if the less soluble
forms of the salt are used.

Rapid action is best obtained by administration of the soluble
salts while fasting; gradual and prolonged action by the less
soluble salts given during or after meals. Under the latter
circumstances the quinine in the circulation may be maintained
at a considerable level for as much as eight hours.

As a rule, from two-thirds to three-quarters of the quinine
introduced into the organism is destroyed by the metabolic
processes of the body, and, through them, is probably deprived

* MacGilehrist (A. C.): Quinine and its salts; their solubility and
absorbability. Paludism, Simla, 1911, No. 2, 27-30.

MALARIAL FEVER 291

of most if not all of its activity. It has generally been assumed
that one may estimate fairly well the efficacity of our methods
of giving quinine by the amount eliminated as such by the urine
and feces. Giemsa and Schaumann ** appear to have shown
that a given quantity of quinine administered daily in several
fractional doses is eliminated more completely than a similar
amount administered as a single dose (23.8 per cent.: 27.8 per
cent.). MacGilchrist, however, asserts that larger doses
administered three times a day give better results in treatment
than fractional doses administered at two-hour intervals. The
same observer, estimating the absorbability of quinine by the
study of the minimal lethal dose in guinea pigs, arrives at
essentially the same conclusions as Mariani?" and Giemsa and
Schaumann, who studied only the urinary elimination. Accord-
ing to MacGilchrist quinine is absorbed best: (1) subecu-
taneously, in solutions of a dilution not less than 1 to 150; (2)
in soluble form by the mouth on an empty stomach; (3) by
the mouth with or just after a meal; (4) subcutaneously in the
ordinary dilutions 1: 2—1: 8.

The first method is, of course, impossible. Subcutaneously
in the ordinary dose, the absorption of quinine is not very com-
plete, for a large proportion of the salt is precipitated in com-
bination with proteid substances. But, practically, this method
of administration is often necessary to obtain immediate action
in individuals with pernicious malaria, where the drug cannot
be administered by the mouth.

Here one is obliged to resort to subcutaneous or better deep
intramuscular injections of soluble salts, of which the dihydro-
chlorate is unquestionably the best, in doses no larger than
1 Gm. diluted in the proportion of 1 to 10.

The most rapid method of introduction of quinine is, un-

* Giemsa and Schaumann: Pharmakologische und chemische Studien
iiber Chinin. Arch. f. Schiffs u. Tropenhyg., Leipz., 1907, xl, 1-83.

*™ Mariani: L’assorbimento e l’eliminazione della chinina e de’ suoi
sali, ete. Atti d. soe. per gli stud. d. malaria. Roma, 1904, v, 211.
Sull’ assorbimento e sull’ eliminazione della chinina e dei suoi
sali, ete., ibid., 1905, vi, 72.

292 HARVEY SOCIETY

doubtedly, the intravenous injection. I have seen cinchonism
produced within a few moments after the injection, while yet
standing by the bedside. But the intravenous injection of
quinine in the ordinary doses and dilutions is not devoid of
danger, and MacGilchrist insists that it should never be given
in dilutions less than 1 to 150. This, however, is perfectly
possible and easy to do in an emergency.

By the mouth, it is better to give the salts of quinine in
solution rather than in capsules, and the salt most fitting for
this method of administration is the dihydrochlorate, which is
soluble in less than its own volume of water. The salt most
commonly used in this country, the sulphate of quinine, may
however easily be administered in solutions to which a little
diluted hydrochlorate or sulphuric acid is added.

The objections raised by MacGilchrist to the administration
of soluble salts in tablet or capsule form, that they may cause
gastric disturbances, is, as a matter of fact, more theoretical
than real, and except in urgent cases quinine may be given in
this fashion with wholly satisfactory results.

From these considerations it is easy to see that the form and
manner in which one gives quinine should vary according to the
conditions existing in the patient. It has been a time-honored
custom in intermittent fever to administer quinine in an inter-
mittent manner. Torti advised large doses in the period
immediately preceding the paroxysm. Sydenham gave large
doses immediately after the paroxysm. Experience shows that
to obtain the most rapid action it is well to have quinine in the
system at the time of the paroxysm, namely, at that period
when the fresh young brood of merozoites is present in the
circulation. Practically, however, excepting in pernicious
cases, experience to-day favors the administration of quinine
in regular, daily, broken doses at frequent intervals. As
Mariani and Giemsa and Schaumann have pointed out, a
steady quantity of quinine may then be maintained in the cir-
culation without the discomfort often following individual
large doses.

Single doses of more than 1 Gm. (gr. xv) are never neces-

MALARIAL FEVER 293

sary, and in all excepting pernicious cases, 2 Gm. (gr. xxx),
in fractional doses of 0.32 Gm. (gr. v) every four hours, are
quite sufficient.

The length of time under which treatment should be con-
tinued varies materially with the case. For ordinary tertian
fever in temperate climates, the dose may soon be reduced to
1 Gm. a day, and, in the course of a few days, to one-half that
amount. But in this quantity it should be continued for long
periods of time, not less than three months. In this way alone
may we hope to avoid a large percentage of relapses.

In estivo-autumnal fever it is often necessary to continue
treatment with as much as 2 Gm. (gr. xxx) a day for a week,
and the diminution of doses thereafter will depend largely upon
the appearance or non-appearance of crescents. Darling *®
appears to have shown that 2 Gm. a day will reduce the gametes
of wstivo-autumnal parasites to a non-infective minimum* in
two or three weeks.

To one who has not observed it, the difference in the
efficacity of treatment in an individual on his feet and attending
to his affairs, and in one who is kept at rest in bed is ineredible.

It is always desirable that a patient with malarial fever
should be kept in his bed until all symptoms of fever have
gone. It is highly desirable that the patient with estivo-
autumnal fever should be kept in his room until gametocytes
have been reduced to a non-infective minimum. The recent
observations of Thompson 7° emphasize the importance of vigor-

* Darling concludes from experimental studies, that patients with
more than one erescent to every 500 leucocytes, or 12 to a cu. mm.
of blood, are infective. If the crescents are scantier than this there
is little chance of their developing in the mosquito.

* Darling: Transmission of Malarial Fever in the Canal Zone by
Anopheles Mosquitoes. J. Am. M. Ass., Chicago, 1909, lini, 2051-
2053.

™Thompson (D.): I. Research into the production, life, and death
of crescents in malignant tertian malaria, in treated and un-
treated cases, by an enumerative method. Annals of Trop. Med.
and Parasitol., Liverp., 1911, Series T. M., v, 57.

294 HARVEY SOCIETY

ous initial treatment of a patient with exstivo-autumnal gam-
etocytes in his blood.

The patient with fever or with demonstrable malarial para-
sites in his blood should always be isolated and protected with
a net. A regular daily search for mosquitoes should be made
in the house, and every method for their extermination by traps
and fumigation should be employed.

All evidence goes to show that it is only by treatment con-
tinued through long periods of time, that relapses can be pre-
vented, and even then a certain percentage of cases, especially
of tertian malaria, reawaken with the succeeding season.

How are we to recognize the early relapses and latent in-
fections? Only by careful observation of the patient, by the
study of the temperature, by frequent examination of the
blood, and by determining the presence or absence of splenic
enlargement. This latter method has been much employed,
following the investigations of Koch, and it is of very con-
siderable value in the carrying out of large public measures
of prophylaxis. It is, however, obviously a much more uncer-
tain procedure than that of careful examination of the blood.

A very remarkable observation has recently. been made by
David Thompson,*® which, if confirmed, may be of real assist-
ance in the recognition of latent cases. Ordinarily in acute
malaria there is a leucopenia, but in latent malaria, where the
number of parasites sporulating is small, there is a leucocytosis
which increases, at the time of sporulation, to a very remarkable
degree. Thompson has found often from 30,000 to 50,000
leucocytes, and once even 125,000, a leucocytosis which rapidly
falls after the period of sporulation. In acute malaria the
relative proportion of mononuclear leucocytes is low at the time
of the paroxysm, becoming high with the fall of temperature
and apyrexia; this same fluctuation persists without regard to
the total number of leucocytes for months, even years, after
apparent cure.

” Thompson (D.): II. The leueoeytes in malarial fever. A method
of diagnosing malaria long after it is apparently cured. Ann.
Trop. Med. and Parasitol., Liverp., 1911, Series T. M., v, 83.

MALARIAL FEVER 295

As has been said before, the corner-stone of the edifice of
malarial prophylaxis is the work of the individual practitioner
in protecting his patients and in detecting and properly disin-
fecting the affected individual. But while nearly every case of
typhoid fever, yellow fever, or cholera falls into the hands of
a physician, and while in most of these diseases the danger is
over with the disappearance of the acute symptoms of the
malady, in malaria the condition is radically different.
Immense numbers of patients in rural districts never consult
a physician, and many more, imperfectly treated, are carriers
of the disease through long periods of time.

The question, therefore, is not purely one of thorough treat-
ment; in every malarious district the healthy must be protected
from the dangers of infection, which are always more or less
present. The duties of the individual practitioner toward the
patient and the general public are therefore greatly com-
plicated.

Let us consider, first, the question of the measures of
individual prophylaxis which one should adopt when in a
malarious region.

A. The first principle is the avoidance, so far as possible,
of infected houses or infected individuals. The hunter or
traveller in the wilds should, when possible, avoid sleeping in
recently inhabited houses. A tent so far removed as possible
from the infected population is the safest place.

B. The house and the bed should be thoroughly netted, the
house, if possible, with wire netting. The bed net should be
strong and should never be allowed to fall to the floor, but should
always be tucked under the mattress. Loose folds shut out the
air. The meshes should not be too large. Eighteen threads to
the inch (seven to the cubic millimetre) are sufficient. There
should be no slit for entering. The substance should be white,
so that the insects may readily be detected. Holes are fatal.

C. The thoroughly netted house should be searched daily
for mosquitoes. This should be the regular duty of some mem-
ber of the household. These may be killed by hand and may
be caught from ceilings or walls by a small butterfly net on a

296 HARVEY SOCIETY

pole. In some instances fumigation may be desirable. This
may be carried out as follows: **

‘“‘To fumigate a room thoroughly for mosquitoes all the
chinks in the doors and windows should be closed by pasting
paper over them. Then burn the culicide as follows (Sir
Rubert Boyce) :

“1, Sulphur. Allow 2 Ibs. of sulphur to 1,000 cubic feet.
Use two pots, place them in a pan containing 1 inch of water
to prevent damage, and set fire to the sulphur by means of
spirit.

“Duration, Three hours.

‘2. Pyrethrum. Allow 3 lbs. to 1,000 eubie feet, and divide
amongst two or three pots, using the same precautions as with
sulphur.

“Duration, Three hours.

‘3. Camphor and Carbolic Acid. Equal parts camphor and
erystallised carbolic acid are fused together into a liquid by
gentle heat. Vaporise 4 ozs. of mixture to each 1,000 cubic
feet; this can be done by placing the liquid in a wide shallow
pan over a spirit or petroleum lamp; white fumes are given
off. To avoid the mixture burning, the fumes should not come
in close contact with the flame of the lamp.

‘Duration, Two hours.

‘‘Rew of these methods actually kill the insect. After
fumigation, floors should be thoroughly swept and all stupefied
insects burned.’’

D. One should look out for all stagnant water on ground and
plants, in any receptacle in the neighborhood of the house, ‘‘in
cisterns, drains, gutters, tubs, jugs, flower-pots, gourds, broken
bottles and crockery, old tins, or other rubbish, or holes in trees
or in certain plants, such as the wild pineapple.’’ As Ross
suggests, an inspection of the premises once a week is an admir-
able plan. Cisterns should be screened so that mosquitoes can-
not lay eggs on the surface.

E. For those obliged to work in the neighborhood of in-

si eae op. Dit 59.

MALARIAL FEVER 297

fected localities at dusk and by night, personal protection by
means of nets hanging from the hat and bound about the neck,
thick gloves, etc., have been shown to be of great value, espe-
cially by the Italians, in the case of employees on the State
railways, and by the Japanese army in Formosa.

These methods, however, are most uncomfortable and try-
ing, and very difficult to enforce. Ross points out the consid-
erable value of the ordinary hand fan consistently agitated by
an intelligent individual.

F. Protection by medicinal substances applied to the skin,
such as oil of lavender, oil of citronelle, oil of eucalyptus,
familiar to all fishermen in this country, is of considerable
value where one cannot carry out other precautions. He, how-
ever, who has used these substances by night, knows well their
inconveniences. They soil the bed, and usually give out to such
an extent as to need at least one re-application before morning.

G. Finally, the method of quinine prophylaxis is of really
great importance. There is abundant proof that the regular
ingestion of small quantities of quinine is an excellent pro-
tection against infection. Koch,*? as a result of his East Indian
and African experiences, advised 1 Gm. (gr. xv) every seventh
and eighth day. Such intermittent treatment is, however, easy
to forget, and large doses often cause unpleasant symptoms.
Mariani ** has shown that small divided daily doses accomplish
as much and are easier to take. From 0.4 to 0.6 Gm. (gr. vi to
gr. x) daily in divided doses is usually advised, and in most
eases this prevents infection, particularly if associated with
other measures of protection.

If such methods as these be carried out by the individual
and in the household, there is little fear, even in the worst
regions, of other than occasional mild and easily treated
infections.

It is especially interesting to note that regularly carried out
quinine prophylaxis is as valuable in combating malarial

* Koch: Berichte iiber die Thitigkeit d. Malariaexpedition. Op. cit.
“Mariani: op. cit.

298 HARVEY SOCIETY

hemoglobinuria as it is in the case of any other manifestation
of the disease (Reynaud) .**

But the important point in connection with prophylaxis of
malaria is the question of public measures of protection. Here,
as has already been said, we in America have so far made a
poor showing in comparison to what has been done in other
countries and in our own colonial possessions. Let us for a
moment consider some of that which may be done and has been
done elsewhere.

The measures of public prophylaxis which should be adopted
in a malarious district are many, but unquestionably the most
fundamental are those directed toward the extermination of
mosquitoes. These measures consist:

1. In the removal, so far as possible, of all breeding places,
namely, collections of stagnant water.

2. In the treatment of those collections of water which
cannot be removed in such manner that they are no longer
suitable for the complete development of the larve and pup
of the mosquito.

3. In the removal of all underbrush, grass, ete., which might
serve as resting or hiding places for the insects, from consider-
able areas surrounding all human habitations.

In some localities these procedures alone may suffice to
eradicate the disease.

ISMAILIA

One of the most brilliant examples of the eradication of
malaria as a result of mosquito destruction is the achievement
of Ross ** at Ismailia.

The mosquitoes here all came from a canal which conducts
the water of the Nile to the town, and from the standing water
associated with it. The country surrounding the town is a
desert. The climate is rainless. The canal company is all-
powerful in the government of the town. The flow of water in
“ Reynaud (G.) : La quinine préventive contre le paludisme et la fiévre

bilieuse hémoglobinurique. Marseille méd., 1911, xlviii, 49; 81;

126; 151; 177.

* Ross: The Prevention of Malaria. 8° Lond. (Murray), 1910, 499.

MALARIAL FEVER 299

the canal was regulated; leaks were stopped. The marsh was
drained. Irrigation canals and channels were cleared of weeds
and the water made to run swiftly. ‘‘When a certain garden
had received its proper supply of water, the flow was stopped
and the water allowed to soak in.’’ All receptacles for standing
water were emptied. A regular mosquito brigade visited each
house once a week and treated the cesspools with petroleum.
In September, 1902, this work was begun. By 1906 the disease
was eradicated, as may be appreciated by reference to the
following table : *°

MabariaA AT ISMAILIA.

Years Cases.
ae eee ee eee oa ana
TERT) bd Ee AS eae eerie 1,545
ERT Ses ak os Saisie eteales soi 2,284
TO dete ros Sita chic, s.cissorstelecereeue 1,99
SP a's Gis smi tje'e ee om 1,551—antimosquito war begun.

LOGE eee re erie 1

PAVIA a Li a ra'si gop arst sss el 90

DOE. od Qe eee 37

MISE ci Sescie ware Siete eialers 2S No fresh cases.

NET AMIN ee oct sa ve a cach sy en8 ise e,9 eye No fresh cases.

i. 35 (a eee ere No malaria contracted in Ismailia.

ener 0 ee eee
HAVANA

With the American occupation of Havana in 1909, a gen-
eral cleaning up of the city was undertaken under military
direction, and in February, 1901, Gorgas began his famous
campaign against yellow fever, a campaign the essential feature
of which was extensive mosquito destruction. This work has
been continued since then by the Cuban authorities. As is
well known, yellow fever disappeared from Havana seven
months after the initiation of this work.

The striking effect of these measures on the malarial mor-
tality of Havana may be seen by reference to the following
table:

re ae ee

* Ross: op. cit., 503.

300 HARVEY SOCIETY

Deratus From Mauaria AT HAVANA.

oe DR Re Se ONE SN) OR NA REA A ae PE aS Ro ryt sc 170
LBM a eit ars ctvatare geNeera ka eel en ate ot aad lad aa reue high eran ee este emene 203
MOD titre sie wee scien Dis win Wie tes gla cas aveptar ‘sh al dt im ioe CUakany es uatatemnegst 202
Peaks relegate aise a EME E Bis) ts ol cue: lye, mt fal eat 240
BOOS LS h ic ete eectd on Ge stn's tetas ecb erelete: ule & ehlaherere tener eet one 201
BOO i/8 oe cleo a hiieleinc he aaa et 2\ cht a 2 oa ay eee ian ral la 207
MO Groce aya area arene a Meat aha dal cet ae co ee pee ean 250
SATs) Seal eRe A NMA aie. ay eORec! Woda ble elt a ale 811
USS 55 che svaks ea ley oe rtsuely ae alls iis! SUS tabi ofa el ae eal 910
BOO aia aint atta Sila is te N ret eked fe 6h y ot el auet aaa ene ae 909
OD aie eis aller ee IN Ste Gra aA. sabe, ott PO NRO eee tee sone 325
1S, CASS eR reine eis Pee oan MM naneR PORTA RU IAU Use toMntDiaicye caus oS 151
De alaletstssleie Mia vaah a che Sisvuie stajist' at's/-4 hale erence acu ate 87
PDS ue ES SRAM ES OE cs Rik st ehicioaat athe ar ete 51
A ie alu tieie ellavebede GIN hie abel ala da \y hatin Mitt ah caret ter ata ea 44
Bare naaha sale & clas plsakateu apbysonle iatie: okel abel alineiote ke te thas er ieee 32
MG Fee Lee: 2, ile ire peck Abeer oa tel lia ci is Oper cen cate 26
MOOT inns oracotede che toa n a Bhai soa tena eer ecard eae ee a 23
BON. sat ase tetare: iw w sone as ois vaste leleahoy seus te “ole a aia onan ee 119
DO 5: iaiauis a ianet le aveyate sane ss! Walsh: aevatel oieoatiers ORS aie eNanseeme 6
De ain vase ree) = usin ence eke oes muse eae to at ea ete ten 15

This is unquestionably the ideal method of prophylaxis, and
it may often be carried out successfully, especially in cities and
centres of population. But in large areas of swampy, uncul-
tivated, sparsely populated land such as exist in some of our
Southern States, these measures are difficult in their application
and do not suffice. Here we must combine and concentrate all
known methods of prophylaxis.

PANAMA

The great example of what may be done under such condi-
tions is afforded by the work: of Gorgas at Panama. Here
conditions were as difficult as may well be imagined. The
whole district was terribly infected, not only with yellow fever
but with the gravest forms of malaria. The death rate had
baffled even those enterprising Frenchmen through whose fore-
sight and energy the waters of Europe had been married to
those of the Indies. The population to be dealt with was
a large body of workmen living in the country within half a
mile of the railroad, in small villages and camps and sometimes
in isolated dwellings. Fresh from his work in Havana, Gorgas
was given sanitary control of the Canal Zone in 1904. The
results of his campaign are remarkable. The last case of yellow
fever occurred in 1906. The death rate has steadily fallen

MALARIAL FEVER 301

until it compares most favorably with that of the cleanest of
civilized nations, as may be seen by reference to the following
table:

Deats Rate PeR 1000 INHABITANTS IN PANAMA CANAL ZONE.

RE RE a iat chaos) eial s!aveta 2 ioils shai) dig) @idl's-ala ale o'e/nlerdle s 49.94
Le Eacr ten OR Rr A ES Shine nenote Goer rac nee 48.37
none Lo oO TAMAS BSE CARER ate SHEE oie a BO oa 33.63
ROM PRI ap ea cee ay doe jac al dle aough secs 6 os ale) Seabees 24.83
nr Aah eas cy ciate fare sco "alial's/ a aiahe Asti ho, oes sides 18.19
MEMEO rt eae See eka ele hea: oct nle a thc oie Gals whaler a oe 21.18
een Meret er Shas cle cp Gia diet o'e\( de) a\'shayatelelayela Sis s «\ele'avele ode lel a%e 21.46

The deaths from malaria have fallen from 16.21 per thou-
sand in July, 1906, to 2.58 per thousand in December, 1909.

Among employees the deaths have fallen from 11.59 per
thousand in November, 1906, to 0.99 per thousand in Novem-
ber, 1911.

The admission rate per thousand among employees to the
hospitals for malaria has fallen also in a most encouraging
manner.

ApMIssiOoN RatE To HospiraLs FOR MALARIA.
(Per Thousand) Canal Zone.

EN COR OR ee AK cin a clags fon eld nts ao) orang’ syn, ole aia’ sc mlminnatn\S 125
MRE etches te oh el cfare Me atrial ss cias cialis’ 0. Seale Smiles eietote ails 514
RE TR DET e ci disiy coe Siottha tls cis-uye iesibia late, » elerakactane $21
Melis Fe no Sn ade she (ahinls fu dvoisvaliaias » Maktlena oY aid sacapeie 424
cesta Myce cao e Ne cl ait, seh dionaieie's’ 4 Care aie, ween 282
-l2 oe Sie Sobel MALE aie Arne De ER Sy UPS PR CaS Sk 215
FRED (Devnet ay evaye tes ate 0 cue sn, sy clap dekedni cts ioheyavetct als.odeyetetege aie) che’ Gig 187
TMM raat aces AG se¥os! crac shane a afala) atevero soap iatata caterers ele ¢ 184

The cost of this sanitary work in the canal for a population
amounting to something over 100,000 inhabitants is $3.50 a
head, of which about $2.00 is spent on anti-malarial work.

And this work is but a beginning. A sure and steady im-
provement must follow its continuance. A certain relapse to
the old conditions will follow its abandonment.

A word as to the nature of this work perhaps is worth while.
The 47 miles of the Panama strip are divided into 18 districts,
each under the control of an inspector, under whom are em-
ployed 50 men.

Drainage.—All pools within 100 yards of individual dwell-
ings or within 200 yards of villages are done away with either
by subsoil or open (concrete if possible) ditches.

302 HARVEY SOCIETY

Brush and Grass Cutting—Within the same areas all trop-
ical undergrowth is cut. Brush and grass shelter adult mos-
quitoes, while anophelines will not as a rule cross a clear area
of 100 yards.

Oiling is used where drainage is impracticable. Where oil
will not spread, a poison which is called ‘‘larvicide’’ is used.
This consists of crude carbolic acid, resin, and caustic soda.

Quinine in prophylactic doses is offered to all employees.

Screening is carefully carried out on all government build-
ings.

Killing Mosquitoes.—Each morning all mosquitoes found in
buildings are killed by special men.

ITALY

Conditions not dissimilar to those in the United States
exist in Italy, where the problem has been approached in a
somewhat different manner. Here, as everywhere, the main
mortality occurs among the peasants, especially on rice planta-
tions and in the fields, in the army, and among the employees
of the railways, who are obliged to live in infected and un-
healthy localities. In 1890, a Society for the Study of Malaria
was founded, supported by contributions of generous citizens
headed by the Queen.

Inspired by the activities of this society presided over by
one whose name has long and honorably been identified with
the study of this disease,* a most important and active cam-
paign has been conducted.

While endeavoring in every way to educate the public and
to encourage all measures directed toward the destruction of
mosquitoes, their larve, and the breeding places, the society
at the outset directed its attention especially to personal and
household protection from the bites of mosquitoes, and later
toward quinine prophylaxis.

The experimental demonstration of the value of the netting

*Prof. Angelo Celli. The work done by this society is presented
annually in the admirable Atti della Soc. per gli studi della Malaria,
and is summed up at the end of each volume by Prof. Celli.

MALARIAL FEVER 303

of dwellings and the personal protection against the bites of
mosquitoes, carried out by this society, has already been men-
tioned. Its impracticability, however, on a large scale in rural
communities, was early recognized, and the great value of
quinine prophylaxis under such circumstances has been admir-
ably brought out by the Italian campaign.

By means of lectures and demonstrations and publications
widely distributed, and with the help of many district phy-
sicians and school masters, and through the formation of local
anti-malarial committees, a campaign of education has been
steadily conducted for over ten years,

In 1902, at the instigation of the society, the State began
the manufacture of quinine, which is placed on sale at every
tobacco store in Italy. The price is nominal. The preparations
are pure and easy to take, and are supplied gratuitously to the
needy, partly through the funds of the society and partly as a
result of laws recently passed by the government, through which
the profits from the manufacture of the drug, already consid-
erable, are employed in furthering the anti-malarial campaign.
The results as set forth by the following table are most
striking:

Iraty:* STATE QUININE AND MORTALITY FROM MAtLariA.

Consumption of State Quinine Mortality from Malaria. Net profits of

___| Adminstration

of State Qui-

Financial Year | Kilograms Sold Solar Year Total Death | nine in Lire.

2 Qhte Seen ooo 1895 16,464 ey eS
SARC DE) eee 1896 14,017 is) aneiets
Saale eee 1897 11,947 ea
SONG Cun ee 1898 11,378 eas
ee GN: eh Busters S's 1899 10,811 tere
oo 6, Son See 1900 15,865 Beale
i Senet ae Giro 1901 13,861 Sette
1902-3 2,242 1902 9,908 34,270
1903-4 7,234 1903 8,513 183,039
1904-5 14,071 1904 8,501 183,382
1905-6 18,712 1905 7,838 293,395
1906-7 20,723 1906 4,871 462,290
1907-8 24,351 1907 4,160 700,062
1908-9 23,635 1908 3,463 769,809
1909-10 21,656 1909 3,535 720,000

*Compiled from Atti della Soc. per gli stud. della Malaria.

304 HARVEY SOCIETY

An especially valuable part of the work of the Italian So-
ciety for the Study of Malaria has been the preparation of
chocolate confections of tannate of quinine. The tannate, a
salt but slightly soluble and rather slow of absorption, is never-
theless absorbed in the end nearly, if not quite, as completely as
the more soluble preparations. The cioccolatium, agreeable to
the taste and practically free from the bitterness of quinine,
are peculiarly valuable in connection with large general
measures of prophylaxis, as they are well taken by children.
The objection that the constitution of the preparation is sub-
ject to some variations in its quinine content has little impor-
tance in the light of the Italian experiences.

The work in Italy to-day has opened up to agriculture
regions which had previously been practically abandoned, and
is saving, as may be seen from the chart, thousands of lives
every year.

GREECE °7

In Greece, in 1903, a similar league was formed which is
doing good work. The studies on the Plain of Marathon em-
phasize the value of small, daily, prophylactic doses of quinine
in association with other measures, while other studies in the
same region have furnished an excellent demonstration of what
may be accomplished by careful diagnosis and thorough treat-
ment alone.

INDIA °°

The British Government in India has recently started a
campaign of a similar sort, the results of which must soon be
apparent. A conference was held in October, 1909, at Simla,
at which there was founded a committee for the study of

* Savas (C.): Le paludisme en Gréce, ete. Atti d. Soe. per gli stud.
della Malaria. Roma, 1907, viii, 136-170. Also, similar communi-
cations in the same publication: 1908, ix, 95-105; 1909, x, 291-
298; 1910, xi, 129-136.

*Paludism, being the Transactions of the Committee for the Study
of Malaria in India. Simla, No. I, July, 1910.

MALARIAL FEVER 305

malaria in India. The organization of the campaign in abstract
was as follows :*°

1. A committee in each province of three or more members,
personally interested in the malaria problem, enjoying the
confidence of the local government and prepared to obtain and
supervise local inquiries. They should perhaps control the
agency for the distribution of quinine. One of their first duties
would be (in association with provincial sanitary department)
to ascertain the real causes of death in different localities, and
to set in motion an inquiry in each district regarding the rela-
tion of the fever season to the drainage and rainfall.

2. Every autumn each provincial community would dele-
gate, under the orders of the local government, one of their
members to attend a meeting of a general committee in Simla.
This general committee would consist of the provincial delegates,
the sanitary commissioner representing the Governor of India,
with Major James as Secretary. The Government of India
would appoint a general scientific committee. .....

A class of instruction was held in March, 1910, presided over
by one of the members of this general committee, which was
attended by various medical officers and subordinates from each
province. This work has been most valuable. At the first
meeting, a series of special subjects to be inquired into was
settled upon and the reports which are appearing in a publica-
tion entitled ‘‘Paludism,’’ edited by the scientific committee,
already contain much valuable material.

There can be little doubt that this movement will bring
great results in India.

In many other regions, especially in Algiers and in British
and German Colonial possessions, enlightened campaigns
against malaria have been conducted with excellent results.

AMERICAN CONDITIONS

When, however, we turn to our own country, we find, alas,
that but little has been done. Local anti-mosquito campaigns
undertaken here and there, of which those in the neighborhood

* Abstracted from Paludism, op. cit.
20

306 HARVEY SOCIETY

of this city have been notable, have had good results. Loeal
attempts at educational movements, of which that conducted
by Dr. Lankford *° in San Antonio, Texas, is a striking example,
have been of great interest and are most creditable.

In Pennsylvania *! and Florida ** special bulletins have been
issued by the State societies and, in the latter State, a most
creditable beginning has been made toward a thorough State
campaign. Nowhere, however, have systematic anti-malarial
measures been taken on any large scale.

The first problem which confronts us when we consider the
steps which should be taken is as to the determination of the
prevalence and distribution of the disease. Here, immediately,
we meet with a difficulty. We know that malaria exists in
certain parts of New England and New York; that it increases
in prevalence along the coast, southward; that it prevails with
particular virulence in the Mississippi Valley and in the val-
leys of its tributaries; that it occurs to a certain extent on the
Pacific Coast and about the great lakes. The conditions asso-
ciated with registration of morbidity and mortality are, how-
ever, so imperfect that it is a difficult matter to form an
adequate idea as to the malarial mortality, not to speak of
the morbidity.

In the interesting study by the Florida State Board of
Health, it is estimated that the rural malarial death rate for
the South for 1908 was approximately 54.52 per 100,000 inhab-
itants, or 11,326 deaths. The registration of the deaths in
this area is so imperfect that this is but an estimate. But if
this estimate even approaches the truth, it is probably safe to
say that the actual mortality in this country is as high as
10,000 a year, and probably considerably greater. And _ be-
side these fatal cases, there is an enormous number of individ-

“Lankford (J. S.): Public School Children and Preventive Medicine.
N. York M. J. (ete.), 1904, Ixxx, 1124-1126.

“Malaria: How it is Caused and How to Get Rid of It. Pa. Health
Bull., Harrisburg, March, 1911, No. 21.

“Malaria: Its Prevention and Control. State Board of Health of
Florida. Publication 84, Jacksonville, June, 1911, pp. 1-43.

MALARIAL FEVER 307

uals, hundreds of thousands certainly, whose lives are made
miserable and whose physical and moral development are re-
tarded and perverted by a preventable and easily treated
disease; and we, as a people, with just pride in what we have
done in Havana and Panama, sit complacently and allow this
to go on.

A few years ago, it was discovered that much of what had
been called malaria in the South was in reality due to infection
with the hookworm—Necator Americanus—and straightway,
through the philanthropy of Mr. Rockefeller, a commission was
established, which, working in unison with State boards of
health through the South, is doing a great work in the eradica-
tion of this plague.

But the old plague, that which calls for a greater toll of
human lives every year, a malady easily prevented and easily
treated, still holds its sway practically unattacked. It is the
old story that ‘‘familiarity breeds contempt.”’

That no more general measures are taken in this country for
the study and control of malaria is a national disgrace.

The problem is one which demands national consideration.
Although the actual prophylactic measures must, under our
form of government, be undertaken by State and local author-
ities, the first step should be a wide-spread and general study
of conditions as they exist in the various localities.

Harris of Mobile and recently Craig *? of the Army have
suggested the formation of a national commission for the study
of the disease. The creation of such a commission would be
an admirable plan.

Just such measures as this would be rendered possible by
the establishment of that National Bureau of Health so urgently
necessary and so long struggled for by all who have the health
and welfare of the community truly at heart. Such a commis-
sion working in harmony with the health authorities of the

Se EE

“Craig (C. F.): Important Factors in the Prophylaxis of the
Malarial Fevers. Southern M. J., Nashville and Mobile, 1912,
50-57.

308 HARVEY SOCIETY

various States could rapidly accomplish results of inestimable
value.

For the accomplishment of much that is to be desired in
the attempt to control malaria in this country, the initiation
of a popular campaign, a campaign of education, is absolutely
necessary.

This might be accomplished through the establishment of a
National Society for the Study and Prevention of Malaria, a
society analogous to that existing in Italy. Such a society might
be formed as an adjunct to a national or endowed commission.
It would, in the beginning, have to depend upon individual
subscriptions as in the case of the Italian organization, and
these would have to amount to an appreciable sum, if it were
hoped to enter immediately upon valuable work. But if a
foundation could be established, such as that which exists for
the study of the hookworm problem, it would be safe to proph-
esy that within a few years the results in the saving of human
lives would be very appreciable. Such an organization should
have its central office somewhere in the midst of a malarious
country, 7.e., in the South. An excellent place would be in
New Orleans, a great centre in the immediate neighborhood
and within easy access of gravely malarious districts. More-
over, New Orleans is already the seat of a school of tropical
medicine. The campaign should be deliberately planned under
the direction of a carefully chosen and well qualified and
salaried director. The first point for study would be the dis-
tribution of malaria in one State after another. This work
should be undertaken in connection with the local health
authorities, as is being done by the hookworm commission.
Through the foundation of a central Society for the Study and
Prevention of Malaria, with branch organizations in each State
analogous to the anti-tuberculous leagues or to the excellent
organization in India, a vigorous campaign of education should
be conducted.

It is especially important to instruct, to interest, and to
enlist the support of school teachers and later to arrange for
systematic instruction of the children. In this connection one

MALARIAL FEVER 309

cannot do better than quote the words of Craig :** ‘‘The teach-
ings of the essentials of malarial prophylaxis in public
schools, in regions in which these fevers are endemic, is a most
useful method of public education. The young are receptive
and there is no better way of interesting the parent than by
instruction of the children. Not only is this true, but what one
learns in youth becomes a matter of habit and will be prac-
ticed throughout life. The adage that ‘You cannot teach an
old dog new tricks,’ is often exemplified when attempts are
made to instruct the adult population in modern views of the
etiology and prophylaxis of disease, and for this reason it is
most important that the young be thoroughly taught regarding
the prophylaxis of malaria.”’

Above all, it should not be forgotten that an educational
campaign of this nature has a far wider effect than the in-
fluence upon the specific malady against which it is directed.
It should and would lead to the more general instruction in
publie schools as to matters of general and personal hygiene,
and such instruction, if given in the proper manner, not by dry
lectures and recitations but by practical demonstration, cannot
fail to go far toward making this country a better and safer
place in which to live.

By such a campaign the interests of the community would
soon be awakened, and active public support would be gained
for measures insuring proper registration of the malarial mor-
tality and morbidity, as well as for active prophylactic
procedures.

But it is not only in spreading the propaganda that chil-
dren may be of use in an active anti-malarial campaign. They
may at times be employed in putting into effect some of the
fundamental measures of malarial prophylaxis. School chil-
dren, in the course of their instruction, may be of real assist-
ance in detecting the breeding places of anophelines—as is
testified to by the interesting results obtained in San Antonio
under the leadership of Lankford.*®

“Craig: op. cit. er
“Lankford: op. cit.

310 HARVEY SOCIETY

There is another interesting manner in which a good deal
might be accomplished. The organization of Boy Scouts is
spreading rapidly through the country. But no part of the
instruction of the soldier is more important than that which
relates to the hygiene of the encampment. The employment
of boy scouts in the course of their instruction in the detec-
tion of the breeding places of anophelines, as has already been
attempted in Pensacola,*® perhaps, indeed, in the actual treat-
ment of these localities, might well be of great assistance in
local anti-malarial campaigns.

Exactly how the work of such a society alone, or better as
an adjunct to a central commission, might best be accomplished
could be determined only as the investigation continued. In
some regions, the main prophylactic effort would probably be
directed toward drainage and mosquito destruction; in others,
toward measures of personal protection and quinine prophy-
laxis. It is, however, quite certain that the first and principal
work would be one of investigation and education. So soon as
our legislators—and that means the people—understand the
true conditions, just so soon may they be counted upon to lend
a hand and assist in the good work. It is the belief of the
speaker that the establishment of a scientific commission, ap-
pointed by the Government or established through private
endowment, for the study and prevention of malaria, supported
by an active popular campaign conducted by national or State
anti-malarial leagues, would bear results of no less brillianey
than those which have been accomplished in other parts of the
world. And this means the annual saving of thousands of
human lives and the restoration to health of hundreds of thou-
sands of suffering human beings, with all the influence that this
has on the physical and moral character of the race and on the
efficiency and prosperity of the community.

I have said before, and I wish to repeat it now, that no
more measures are taken in this community for the study and

“Malaria: Its Prevention and Control. State Board of Health of
Florida, Publication 84, June, 1911, 30.

MALARIAL FEVER 311

control of malaria is a national disgrace. Such a condition
could not long exist with an efficient National Bureau of
Health, through which the initiative in the necessary statistical
investigations and suggestions as to the proper prophylactic
steps should come. That no such body should exist in our
country to-day is a sad reflection on the general intelligence and
education of the public. But if we are not as a community
sufficiently intelligent to realize that the health of our fellows
approaches in importance that of the sheep and the hog so dear
to our representatives in Congress—that is to us—it is well at
least for us as physicians to recognize the fact and to do what
we can to show the way.

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Biclogical
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Harvey Society, New York
The Harvey lectures

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